MedChemCASES | Gesellschaft Deutscher Chemiker e.V. (2023)

MedChemCASES ist eine im Jahr 2020 gestartete Online-Seminarreiheder GDCh-Fachgruppe Medizinische Chemie, in deren Rahmen Fallstudien aus Industrie und akademischer Forschungslandschaftpräsentiert werden. Das Programm wird konzipiert in Zusammenarbeit mit der Gruppe



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MedChemCASES #25: Dr. Soufyan Jerhaoui

Dr. Soufyan Jerhaoui(The Janssen Pharmaceutical Companies of Johnson & Johnson)
June 27, 2023
5PM (Berlin time, CET)

Registration link:

Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies

Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the “non-Lipinski” beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability in vivo and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model.

MedChemCASES #24: Prof. Dr. Oliver Hantschel

Prof. Dr. Oliver Hantschel
May 16, 2023
5PM (Berlin time, CET)

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Targeting oncogenes with allosteric inhibitors and engineered monobody proteins

Over the past two decades, more than 70 ATP-competitive kinase inhibitors were approved for the treatment of patients with haematological and solid tumors. Despite this remarkable progress, the development of drug resistance severely blunted initial clinical responses. An alternative strategy is the identification and targeting of allosteric sites that are critical for oncogenicity. This could decrease drug resistance, as the allosteric site could be targeted alternatingly or simultaneously. The BCR-ABL fusion tyrosine kinase is the driving mutation of chronic myelogenous leukemia (CML) and some acute lymphoblastic leukemias. Our detailed studies of the structure and regulation of BCR-ABL have led to the identification of the allosteric myristoyl binding pocket that is critical for BCR-ABL-dependent oncogenic transformation. I will present how based on these insights, small-molecule myristoyl pocket inhibitors were developed, of which asciminib was recently approved for the treatment of CML patients.

In the second part of my presentation, I will present how monobodies can be used to target protein-protein interactions of key oncogenes. Monobodies are synthetic in vitro-evolved binders built on the fibronectin type III (FN3) domain. They are only ~10kDa in size, lack cysteine residues and can bind their target proteins with low nanomolar affinity. We extensively use monobodies to target key nodes of oncogenic signaling networks: These include BCR-ABL, the oncogenic SHP2 and SHP1 tyrosine phosphatase, the SH2 domains of Src family kinases, the transcription factors STAT3 and STAT5 and the E3 ubiquitin ligase c-Cbl. I will focus on our efforts in converting monobodies from potent pre-clinical target validation tools to next-generation protein-based therapeutics by developing approaches to deliver monobody proteins to cells and to engineer mirror-image D-monobodies.

MedChemCASES #23: Dr. Benjamin Horning

Dr. Benjamin Horning
April 26, 2023
5PM (Berlin time, CET)

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Industrialized chemoproteomics enables the discovery of allosteric modulators of Janus Kinase 1 and Cereblon targeting novel sites

Interest in covalent inhibitors has seen a resurgence in recent years, owing in large part to proteomics technology to assess selectivity and de-risk off-target concerns. We have utilized our proteomics platform to guide the development of a screening library containing small molecules armed with covalent reactive groups. From these efforts we have discovered inhibitors of Janus kinase 1 (JAK1) that potently and selectively inhibit JAK1 mediated cytokine signaling through a novel allosteric pocket on the pseudokinase domain, distinct from the pocket bound by recent clinical stage inhibitors of the related kinase Tyk2. We demonstrate that our inhibitors function via inhibiting trans-phosphorylation of JAK1 via its heterodimeric JAK family member, a key step in the signaling cascade. These covalent, allosteric JAK1 inhibitors avoid the selectivity issues common to traditional kinase inhibitors, which bind to highly conserved kinase active sites. Moreover, since the target cysteine in JAK1 is not highly conserved, they have the potential to avoid potential clinical safety issues associated with inhibiting off targets such as JAK2. In addition, we have discovered a novel pocket on the E3 ligase Cereblon that can be targeted by covalent molecules. Binding to this pocket allosterically prevents imide binding, and the allosteric relationship between these two sites can be utilized to monitor imide binding to Cereblon in bifunctional molecules.

MedChemCASES #22: Dr. Brian Lanman

Dr. Brian Lanman (Amgen)
February 15, 2023
5PM (Berlin time, CET)

Registration link:

Inhibiting KRAS: Strategies, Structures, and Lessons Learned in the Invention of Sotorasib

KRAS is one of the most frequently mutated oncogenes in human cancer. Despite more than three decades of research, indirect approaches targeting KRAS-mutant cancers have largely failed to show clinical benefit, and direct approaches have historically been stymied by the apparently ‘undruggable’ nature of KRAS. In this case study, I’ll describe efforts at Amgen to identify cysteine-reactive molecules capable of selectively inhibiting a prevalent mutated form of KRAS, KRASG12C. These efforts leveraged iterative screening and structural biology studies, property-based optimization, and careful process engineering to deliver a highly potent and selective covalent inhibitor of KRASG12C: sotorasib (LUMAKRAS®/LUMYKRAS®). I'll also describe structural insights into the allosteric inhibition of KRASG12C and their implications for inhibitor efficacy and selectivity.

MedChemCASES #21: Dr. Stefan Gradl

Dr. Stefan Gradl (Bayer AG)
January 24, 2023
5PM (Berlin time, CET)

Discovery and structure activity relationships of BAY 2666605: PDE3A-SLFN12 complex inducer for cancer therapy

Velcrin compounds are small molecules which act as molecular glues to form a PDE3A-SLFN12 complex. This complex formation induces apoptosis in cancer cells expressing elevated levels of PDE3A and SLFN12 (de Waal et al., Nat Chem Biol 2016; Wu et al., J Bio Chem 2020). Unlike traditional targeted therapies that leverage dependencies created by genomic alterations in cancer cells, velcrins instead kill cancer cells by a gain-of-function mechanism dependent on stimulation of SLFN12 RNase activity by complex formation with PDE3A (Garvie et al., Nat Commun 2021).

Based on in-vivo tool compounds which were discovered by hit-to-lead optimization from a phenotypic screen (Lewis et al., ACS Med Chem Lett 2019), the team set out to optimize the properties of the tool compounds. While already showing excellent potency and in-vivo efficacy in various tumor models, the compounds were only approximately tenfold selective against PDE3A when compared to their cell killing activity. PDE3A/B activity most notably influences cardiohemodynamics and inhibition of PDE3A/B was to be reduced to generate a larger safety window. Co-crystallization of analogs with PDE3A showed the binding mode of the velcrin class and changes in the solvent exposed region of the PDE3A binders led to steep activity changes in complex formation and cell killing. Careful optimization of the ratio of cell killing to PDE3A activity while optimizing DMPK and safety pharmacology led to the discovery of BAY 2666605.

BAY 2666605 has recently entered a First-in-Human study (NCT04809805) in patients with advanced solid tumors that co-express PDE3A and SLFN12, including melanoma, ovarian cancer, and sarcoma. We will discuss the discovery and structure activity relationships of BAY 2666605.

MedChemCASES #20: Prof. Dr. Anna K.H. Hirsch

Prof. Dr. Anna K.H. Hirsch (Helmholtz Institut, Saarland)
December 14, 2022
5:00 PM (Berlin time)

Addressing unusual anti-infective targets

The challenges associated with anti-infective drug-discovery programmes can be tackled by combining several established and unprecedented hit-identification strategies with phenotypic antibacterial screening. I will illustrate this approach with a selection of un(der)explored targets. The first is a vitamin transporter from the energy-coupling factor (ECF) class, which is unique to Gram-positive bacteria. Here, we report on the structure-based virtual screening (SBVS), design, synthesis and structure–activity relationships of the first classes of selective, antibacterial inhibitors of the energycoupling factor (ECF) transporters with good in vitro and whole-cell activity and a good in vitro ADMET and in vivo PK profiles. A newly established cell-based uptake assay in Lactobacillus casei greatly facilitated our screening and hit-to-lead optimisation campaign. The second is the β-subunit of the bacterial DNA polymerase III (sliding clamp, DnaN), an attractive antibacterial target. We pursued several hit-identification strategies, including a SBVS campaign, affording novel chemotypes with micromolar affinity and promising antibacterial activity. Mode-ofaction studies confirmed DnaN as the molecular target. The new compound displays broad-spectrum antibacterial activity against mycobacteria, Gram-positive and Gram-negative pathogens also against multidrug-resistant bacteria with no cytotoxicity and good in vivo PK profiles. Finally, we succeeded in fragment merging and linking, affording highly selective and potent inhibitors of the extracellular metalloprotease and virulence factor of Pseudomonas aeruginosa, the elastase LasB. Multiparameter optimisation is currently ongoing based on extensive in vitro and ex vivo profiling, including the establishment of complex biological assays. Our approach promises to deliver the urgently needed anti-infective agents featuring both new chemical scaffolds and unprecedented modes of action. Multiparameter optimisation is currently ongoing based on extensive in vitro, wholecell, ex vivo and in vivo profiling, including the establishment of complex biological assays. A particular emphasis will be placed on the lead optimisation of frontrunners for permeation and achieving good lung exposure.

MedChemCASES #19: Dr. Michael Gradl [POSTPONED; cf. #21]

Dr. Stefan Gradl (Bayer AG)
POSTPONED (cf. MedChemCASES #21)

MedChemCASES #18: Dr. Kai Schiemann

Dr. Kai Schiemann (Merck KGaA)
October 26, 2022
5:00 PM (Berlin time)

Discovery of M1069, a highly selective dual inhibitor of adenosine A2a/A2b receptors

While the A2A adenosine receptor has been considered a major contributor to adenosine mediated tumor immunosuppression, the A2B receptor has recently emerged as another potential therapeutic target. Considering the importance of both targets, we developed M1069 as a selective dual antagonist of the A2A and A2B adenosine receptors to counteract the immunosuppressive effects of adenosine signaling and stimulate anti-tumor immune responses in patients with advanced malignancies.

M1069 was discovered through the medicinal chemistry optimization of a thiazolo[4,5-c]pyridin-2-amine scaffold. The binding mode was confirmed by X-ray structure analysis of close derivatives of M1069 in a complex with the A2A receptor domain. Initial cellular optimization resulted in a very high A2AR potency and a low potency for A2BR. Homology models of the A2BR, along with docking into the published A1R, supported further optimization. Increasing the potency on A2BR was a major challenge, which required some fine-tuning of the substituents, while keeping a high split ratio to the A1R, which was defined as an exclusion criterion to avoid unwanted side-effects. Finally, potent dual and selective A2A/A2B antagonists were further profiled. Surprisingly, some of these showed species’ differences in human and murine T cells, as well as myeloid cells at high (10 µM) NECA (stable analog of adenosine) concentrations and needed to be excluded from the evaluation of in vivo pharmacology using murine tumor models. In contrast, M1069 demonstrated dual A2A and A2B antagonist activity in assays with both human and murine immune cells, favorable physchem/ADME properties, good PK in various species and predicted minimal brain penetration in humans.

Preclinically, M1069 has demonstrated superior activity in comparison to A2A-selective reference antagonists in high (10uM) NECA/adenosine settings in vitro, which translated into superior anti-tumor activity for M1069 in vivo in the 4T1 tumor model. In addition, M1069 showed combination activity with the chemotherapeutic agents’ cisplatin and paclitaxel in the 4T1 tumor model. These preclinical data are consistent with a primary mechanism of action of M1069 that involves the reversal of immune suppression via dual antagonism of pro-tumorigenic A2A and A2B adenosine receptors in an adenosine rich TME, where A2B could act complementary, or compensatory to A2A. Together, this data suggests higher potential for dual A2A/A2B antagonism of M1069 compared to A2A antagonism to block the immune-suppressive/pro-tumorigenic impact of adenosine.

M1069 is currently being evaluated as a monotherapy in a Phase I, first-in-human clinical trial in patients with advanced solid tumors (NCT05198349).

MedChemCASES #17: Dr. Nis Halland

Dr. Nis Halland (Sanofi)
September 22, 2022
5:00 PM (Berlin time)

Rational design and optimization of SGK1 inhibitors for the treatment osteoarthritis
The serine/threonine kinase SGK1 is an activator of the β-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today no oral disease-modifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic and safety profile. We describe the preparation of a highly selective druglike 1H-pyrazolo[3,4-d]pyrimidine SGK1 inhibitor that matches both safety and pharmacokinetic requirements for oral dosing. Rational compound design was facilitated by a novel hSGK1 cocrystal structure and classic medicinal chemistry was applied to guide the chemical optimization of ADMET and selectivity profiles.

MedChemCASES #16: Dr. Simona Cotesta

Dr. Simona Cotesta (Novartis)
June 22, 2022
5:00 PM (Berlin time)

Registration link:

Discovery of JDQ443, a structurally novel, potent and selective covalent oral inhibitor of KRASG12C
RAS is the most frequently mutated oncogene in cancer, with KRAS G12C mutations most commonly found in lung adenocarcinoma, colorectal cancer, and other solid tumor malignancies. Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRAS G12C-mutated cancers. Here we report the identification of a new class of pyrazole based KRASG12C inhibitors discovered by structure based de-novo design. The compounds bind to the KRASG12C switch II pocket with a novel binding mode, exploiting unique interactions with the GDP-bound form of the KRASG12C protein. We describe the hit to lead and lead optimization by structure-based design of the novel chemical series leading to the discovery of NVP-JDQ443 (JDQ443), a novel, potent and selective, orally bioavailable KRASG12C covalent inhibitor. JDQ443 showed dose dependent antitumor efficacy in KRAS G12C-mutated cell-derived models and is currently in clinical development as monotherapy as well as in combination with TNO155, a SHP2 inhibitor (NCT04699188).

MedChemCASES #15: Dr. Tim Owens

Dr. Tim Owens (Principia - Sanofi)
May 24, 2022
5:00 PM (Berlin time)

Development of Reversible Covalent Inhibitors as Chemical Probes and Clinical Candidates
In 2013,Serafimova assessed a series of electrophilic molecules that engaged non-catalytic cysteines in a covalent manner, but with variable target residence times, driven by the various stabilizing interactions of the molecule in the protein binding site. These reversible covalent inhibitors were shown to rapidly dissociate from common thiols while maintaining sustained inhibition of a target protein even after washout. This technology, therefore, has the potential to allow medicinal chemists to fashion inhibitors with the potential for selectivity gained by inhibiting only targets with a conserved cysteine, and minimal exposure requirements inherent with covalent inhibition. The reversible covalent approach furthermore mitigates risk of irreversible binding to non-target cysteines or endogenous thiols, but also allows the potential to improve selectivity among targets sharing a common cysteine. This technology has been used to identify selective inhibitors of kinases such as BTK and FGFR as well as LMP7 subunit of the immunoproteasome. Based on our interest in BTK inhibition for the treatment of immune mediated disorders, we embarked on a drug development effort to identify reversible covalent inhibitors culminating in the identification of PRN473 for topical administration and PRN1008 (rilzabrutinib) as an oral BTK inhibitor currently in multiple phase 3 studies.

MedChemCASES #14: Dr. David Battersby

Dr. David Battersby (GSK)
April 28, 2022
5:00 PM (Berlin time)

Registration link:

High-throughput PROTAC synthesis for direct, biological assaying
Direct-to-biology (D2B) synthesis and assaying has the potential to cut drug-discovery cycle times by providing information rich experiments in a highly efficient manner. For PROTACs, this cycle time is often slower than conventional medicinal chemistry as there are a plethora of small molecule E3-ligase or protein-of-interest binders and vectors to investigate as well as a vast landscape of linker chemical space to explore; finding the optimum for these three individual components is time-consuming and resource intensive. An attractive alternative would be to conduct miniaturized reactions in 1536-well plates, where all three PROTAC components are simultaneously evaluated, and directly assessed as crude reactions in cell-based HiBiT assays. Judicious reagents choice is required to ensure high reaction conversion and, moreover, minimize any effect on cell-viability. This talk will showcase our Direct-to-biology protocol to assess crude PROTACs using two well established PROTAC target case-studies: HER2 and BRD4.

MedChemCASES #13: Dr. David Thaisrivongs

Dr. David Thaisrivongs (MSD)
February 23, 2022
5:00 PM (Berlin time)

Synthetic macrocyclic peptides that target protein-protein interactions: the discovery and early chemistry development of a PCSK9 inhibitor
Inhibition of Proprotein Convertase Subtilisin/Kexin type-9 (PCSK9) improves cardiovascular outcomes in patients requiring additional low-density lipoprotein cholesterol reduction on top of statins, but there has been limited uptake of the two commercialized PCSK9 antibody inhibitors due in part to cost and route of administration. The protein-protein interaction between PCSK9 and the low-density lipoprotein receptor which is targeted by these therapies is a large, flat surface, which has made the discovery of orally-bioavailable small molecule inhibitors highly challenging. This talk will introduce the use of macrocyclic peptides to interrupt such protein-protein interactions, and describe the discovery and early chemistry development of such a PCSK9 inhibitor.

MedChemCASES #12: Dr. Jörg Kley

Dr. Jörg Kley (Boehringer Ingelheim)
January 26, 2022
5:00 PM (Berlin time)

Discovery of BI 1265162, an ENaC Inhibitor for the Treatment of Cystic Fibrosis
BI 1265162 is an inhaled epithelial sodium channel (ENaC) inhibitor that reached clinical phase 2. This talk will discuss different approaches to achieve lung tissue selective ENaC inhibition and present how the structure of BI 1265162 evolved from a literature starting point. Besides the need for a long duration of action without renal side effects, physicochemical properties required for administration via the Respimat® Soft Mist™ inhaler guided our compound optimization.BI 1265162 contains a phosphine oxide moiety, and the properties brought in by this less common structural element are discussed.

MedChemCASES #11: Keith Graham

Dr. Keith Graham (Bayer)
November 18, 2021
4:00 pm (Berlin time)

Joint event with the EFMC-YSN, followed by a round table discussion
“Life as a foreign scientists in Germany”.

The seminar is free of charge, butREGISTRATIONis needed.

Discovery of potent SOS1 inhibitors and their pharmacological investigations to disrupt the RAS-SOS1 interaction​
Mutants of RAS are major oncogenes and are prevalent in many human cancers, however efforts to develop drugs that directly inhibit the corresponding constitutively active RAS proteins have been unsuccessful so far, although there are promising new findings for KRas-G12C covalent inhibitors. We focused on SOS1, the guanine nucleotide exchange factor (GEF), and an activator of RAS. We identified good starting points for medicinal chemistry activities using both high-throughput and fragment screens. Initial optimizations resulted in the discovery of the first nanomolar SOS1 inhibitors, which effectively downregulated active RAS in tumour cells. Here, the key findings on our path to identifying novel potent and cellular active small molecule inhibitors will be described. These inhibitors efficiently disrupted the interaction between KRAS and its exchange factor SOS1, this mode of action was confirmed by a series of biophysical techniques. The binding sites, mode of action and selectivity were elucidated using crystal structures of KRASG12C–SOS1, SOS1 and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block the reloading of KRAS with GTP and, therefore, showed antiproliferative activity. Our probe BAY-293 selectively inhibited the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for further investigations. In cells with wild-type KRAS the complete inhibition of the RAS–RAF–MEK–ERK pathway was observed. In a mutant KRAS cell line, SOS1 inhibition resulted in a reduction of pERK activity by 50%. Together, the data indicate that inhibition of GEFs may represent a new viable approach for targeting RAS-driven tumours.

MedChemCASES #10: Stephen Fesik

Name: Stephen Fesik (Vanderbilt University School of Medicine, Nashville, TN, USA)
Date: October 21, 2021, 4:00 pm

Chairs:Chistian Kuttruff,Julien Lefranc
Co-Chair:Franz von Nussbaum

Title:The Discovery of Potent WDR5 Inhibitors for the Treatment of Cancer
WDR5 is a component of multiple epigenetic regulatory complexes, including the mixed lineage leukemia (MLL)/SET complexes that deposit histone H3 lysine 4 methylation. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 has emerged as an attractive target for therapy. We discovered potent WDR5 inhibitors using fragment-based methods and structure-based design. These inhibitors have been optimized for their drug-like properties and show potent oral activity in tumor xenograft mouse models. They act not by altering histone methylation but by displacing WDR5 from chromatin at protein synthesis genes, choking the translational capacity of these cells, and inducing death via a nucleolar stress response. Our inhibitors could thus have broad therapeutic utility as anti-cancer agents.

MedChemCASES #9: Timo Heinrich

Name: Timo Heinrich (Merck KGaA, Darmstadt)
Date : September 23, 2021, 4:00 pm

Chair: Tatjana Ross, Franca Klingler
Co-Chair: Franz von Nussbaum

Title:Discovery and Optimization of Next Generation Reversible Methionine Aminopeptidase-2 Inhibitors – Identification of clinical compound M8891
Co- and post-translational protein processing is important to ensure the maturation tofunctional proteins. MetAP-2 proteolytically removes the amino-terminal methioninefrom nascent proteins, and inhibition of its activity has been shown to blockangiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2may be promising options for the treatment of cancer. This talk describes how
persistence and serendipity helped to identify a previously unknown MetAP-2 inhibitoryscaffold. The biochemical activity of more conventional, purine base compounds didnot translate to cellular activity. Thorough analysis of HTS screening results led tothe identification of chiral tartronic diamide hits. Structure-based hit-to-lead optimizationis out-lined, including different synthetic strategies for most efficient access to improvedderivatives as well as asymmetric approaches. The initial lead compound suffered fromenterohepatic circulation, preventing further development. Binding kinetics wereinvestigated by fluorescence cross correlation spectroscopy and residence time on thetarget protein was one important characterization criterion. Adjustment of H-bonddonor/acceptor count and multiparameter analysis of the compound properties led tothe nomination of the clinical development compound M8891, which impedes thegrowth of primary endothelial cells, shows dose-dependent biomarker modulation andantitumoral activity in mouse xenograft models.

MedChemCASES #8: Stefan Knapp

Stefan Knapp (Universität Frankfurt)
June 24, 2021
4:00 pm (Berlin time)

Chairs: Matthias Gehringer, Eleonora Diamanti
Co-Chair: Franz von Nussbaum

Title: Targeting protein scaffolding function in kinases
In living cells, protein kinases are organized in large signalling complexes comprising adapter proteins, diverse enzymes and regulatory proteins. In recent years it has become increasingly evident, that protein kinases act not only as independent enzymes but that they also function as protein interaction scaffolds organizing the assembly of signalling complexes in a conformation sensitive way. This complexity is also reflected by the response of kinases to inhibitors that may stabilize diverse conformations acting as inhibitors of enzymatic activity only, as modulators of kinase scaffolding roles or both. In this talk, I will exemplify the implications of altering protein interactions by allosteric small molecules as well as canonical ATP competitive inhibitors using a number of selective inhibitors that we developed recently. I will demonstrate how different binding modes that alter protein conformation and dynamics in a distinct way may result in diverse signalling outcomes and phenotypic responses. The important scaffolding roles of protein kinases will also enable targeting new and so far poorly explored members of the kinase family such as catalytically inactive pseudokinases, that represent a considerable number of largely unexplored kinase targets which have been linked to the development of many diseases.

MedChemCASES #7: Cristina Nevado [POSTPONED]

Postponed dueto unforeseen events. The webinar will be rescheduled at a later date. We apologize for any inconvenience.

Cristina Nevado (University of Zurich, Switzerland)
Chairs: María Méndez Pérez, Franca Klingler
Co-Chair: Franz von Nussbaum

"Exploring the chemistry and biology of CREBBP and EP300 Bromodomains"
Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. In this talk we will introduce AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines.

MedChemCASES #6: Jun Liang

Jun Liang (Genentech, USA)
April 1, 2021
4:00 pm (Berlin time)
Franca Klingler, Julien Lefranc
Co-Chair: Franz von Nussbaum

"Discovery of a highly potent and orally bioavailable Selective Estrogen Receptor Degrader (SERD) GDC-9545 for ER-positive breast cancer"
Breast cancer is the most common cancer and second leading cause of cancer death in women. Approximately 70% of breast cancers are ER-positive (ER+). Standard of care therapies include Selective Estrogen Receptor Modulators (SERMs), such as tamoxifen, and aromatase inhibitors. Despite their initial effectiveness, 20-30% of patients eventually relapse, and become resistant due to ER mutations. Fulvestrant, a full antagonist of ER and later found to be a SERD, was approved to treat advanced and metastatic disease. However, fulvestrant is not orally bioavailable and needs to be injected intramuscularly due to its unique pharmacokinetic and pharmaceutical properties. We were attracted by the dual mechanisms of fulvestrant: a full antagonist and an SERD. Herein we report the discovery of GDC-9545, a highly potent full antagonist and orally bioavailable SERD with improved pharmacokinetic and pharmaceutical properties, guided by structure- and property-based designs. In vitro, GDC-9545 showed excellent antagonist potency and consistent ER degradation across ER+ cell lines. In vivo, GDC-9545 demonstrated dose-dependent efficacy in both ER wild-type and mutant xenograft models, achieving tumor regression at 1/100th dose of GDC-0927. Moreover, GDC-9545 did not exhibit partial agonist effect in the uterus of immature rats, and was well tolerated in pilot tox studies. In humans, GDC-9545 showed excellent PK profiles and is currently in Phase III clinical trials.

MedChemCASES #5: Michiel Van Gool

Michiel Van Gool (Janssen R&D, Spain)
January 21, 2021
4:00 pm (Berlin time)
Julien Lefranc, María Méndez Pérez
Co-Chair: Franz von Nussbaum

"The design of mGlu2 NAMs for neuropsychiatricdisorders and tracers for PET imaging"
Glutamate, the main excitatory neurotransmitter in the brain, acts on two distinct classes of receptors: the ionotropic (NMDA, AMPA, Kainate) and metabotropic glutamate (mGlu) receptors. The mGlu receptors play an important modulatory role in neurotransmission and are closely involved in a variety of physiological functions. Preclinical data support the therapeutic potential of negative allosteric modulation of the mGlu2 receptor in neuropsychiatric disorders such as depression and improvement in cognitive function in disorders like Alzheimer Disease.A high throughput screening (HTS) campaign resulted in an attractive pyrazole hit with moderate potency as negative allosteric modulator of the mGlu2 receptor. A focused medicinal chemistry optimization effort led to a lead compound with single digit nanomolar potency.1 Further evaluation of this lead, focused on reducing lipophilicity by means of a drastic change in the central scaffold, led to a pyrazolo-dihydropyrazinone bicycle with improved drug-like properties. Further optimization towards the ideal substitution pattern resulted in the selection of a candidate for clinical evaluation.In parallel to our Medicinal Chemistry efforts, we started a research program to discover an mGlu2 NAM-based PET radiotracer for in vivo imaging of this receptor in brain, applying our reported strategy.2 Several differently substituted derivatives framed within the pyrazolo-dihydropyrazinone bicycle were synthesized, containing motifs that could be eventually radiolabeled either with 11C or 18F. We will present the synthesis and biological evaluation of a set of compounds belonging to this new series of mGlu2 NAMs, and assessment as potential PET ligands of the most promising candidates.

MedChemCASES #4: Darryl B. McConnell

Darryl B. McConnell, PhD (Boehringer Ingelheim Regional Centre Vienna, Austria)
December 3, 2020

4:00 p.m. (Berlin time)
Christian Kutruff, María Méndez Pérez
Co-Chair: Franz von Nussbaum

"Drugging the Top 9 KRAS Mutants"
KRAS drives 1 in 7 of all human cancers. 90% of the KRAS driven cancers are caused by 9 different KRAS mutants. It took 36 years to bring drugs against the first KRAS mutant KRASG12C to Phase 1 clinical trials after Channing Der’s discovery in 1982 that KRAS is an oncogene. It will be discussed why it took so long for medicinal chemists to discoverdrugs against the first KRAS mutant and BI’s learnings from internal efforts against KRAS. Importantly, it will be highlighted what this means for the future practice of medicinal chemistry (MedChem2.0). The talk will also highlight a selection of the multiple approaches that Boehringer-Ingelheim is taking to drug KRAS including pan-KRAS concepts and selective KRAS concepts. The importance of not only inhibiting MAPK pathway signaling but also blocking negative feedback will be emphasized. The practice of MedChem2.0 will be needed to drug the many KRAS mutants yet to be drugged in order to bring medicines to patients with KRAS driven cancers and RASopathies.

MedChemCASES #3 (Special Edition): Oliver Koch, Daniel Merk

Special Edition: Innovation Award 2020
October 28, 2020
4:00 p.m. (Berlin time)
Matthias Gehringer, Franca Klingler
Co-Chair: Franz von Nussbaum

PD Dr. Oliver Koch(Westfälische Wilhelms-Universität Münster, Germany)
“The use of data-driven decisions for rational molecular design”

The increase in the number of protein structures and the enormous amounts of bioactivity data still require new approaches for efficient data mining and knowledge discovery. One focus of my research is (new) data-oriented methods and artificial intelligence for the analysis of protein-ligand interactions and the underlying framework of protein binding sites. The goal is to use this knowledge, the available "big" bioactivity data, and protein structures for computational molecular design and optimization of new bioactive compounds.In the first presented project, our analysis to identify a promiscuous fragment that can be used for fragment-based design approaches is discussed. This result was based on a scaffold analysis of bioactivity data and comparison of binding sites. The second project deals with domain-specific fingerprints generated by neural networks that improve ligand-based virtual screening.

PD Dr. Daniel Merk(Goethe University Frankfurt, Germany)
“Advances in targeting retinoid X receptors”

The nuclear retinoid X receptors (RXR) act as ligand-sensing transcription factors and hold great promise for neurodegeneration and cancer treatment. However, available RXR agonists exhibit severe adverse effects, have poor properties and lack subtype-selectivity hindering exploitation of this therapeutic potential. We have applied diverse strategies to overcome these obstacles in targeting RXRs. We have observed RXR modulation by several approved drugs, the systematic optimization of which produced potent RXR agonists with superior properties. In the search of subtype-preferential RXR ligands we hypothesized natural products (NP) as promising candidates and discovered valerenic acid as selective RXRβ agonist. Computational de novo design provided several NP-derived subtype-preferential RXR ligand scaffolds and revealed selectivity-driving structural features. Additionally, we have solved the first uniform set of RXR co-crystal structures in active conformation bound to an identical ligand as structural basis for selective RXR agonist design. Our results open avenues to new generations of RXR modulators. Obtaining subtype-selective RXR agonists remains a challenge, however.


Innovation Award

is jointly funded by the Division of Medicinal Chemistry of the German Chemical Society(GDCh) and the Division of Pharmaceutical/Medicinal Chemistry of the German Pharmaceutical Society (DPhG), to honor outstan-ding and independentscientific research of young scientists in the areas of medicinal and pharmaceutical chemistry.

MedChemCASES #2: Ed Tate

Prof. Dr. Ed Tate (Imperial College London and Francis Crick Institute)
September 2, 2020
4:00 p.m. (Berlin time)
Gerhard Hessler, Franz von Nussbaum
Co-Chair: Franca Klingler

“Targeting protein modification: from chemical biology to drug discovery”
My group works on a wide range of chemical biology approaches focused primarily on small molecule probes that enable drug target identification and validation. Particularly active areas of research include conditional protein degradation, photoaffinity-driven target discovery, activity profiling of proteases and deubiquitinases, covalent fragment-based drug design, protein-protein interaction inhibitors, and chemical proteomic approaches to understand and target protein post-translational modifications. In this talk I will discuss our work in some of these areas, illustrated with examples of projects which have delivered small molecules into preclinical development.

MedChemCASES #1: Doyle Cassar

Dr. Doyle Cassar (Astra-Zeneca)
July 9, 2020
4:00 p.m. (Berlin time)

Chairs: Gerhard Hessler, Franz von Nussbaum
Co-Chair: Franca Klingler

“Allosteric Covalent Inhibitors of the Mutant GTPase KRASG12C”
Of all human cancers, 20% have a mutation in GTPase KRAS with a high frequency being found in pancreatic, colorectal and non-small cell lung cancer (NSCLC). A glycine to cysteine mutation at codon 12 is the most frequent mutation found in NSCLC, rendering KRAS constitutively active and driving cell proliferation, survival and differentiation. Covalent targeting of this cysteine residue offers the potential for selective inhibitors of the G12C mutant isoform and an allosteric mode of action potentially negates the impact of high nucleotide binding affinity for the GTPase. A knowledge- and structure-based design approach was utilised to derive diverse series of covalent inhibitors that interact directly with this cysteine mutation, causing a shift in the switch II region and rendering KRAS inactive. This talk will highlight our development of a series of candidates with excellent DMPK properties and superior efficacy to other agents targeting this mechanism.

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