MedChemCASES: Online-Seminare der FG Medizinische Chemie

MedChemCASES is a new online seminar series of the GDCh Division of Medicinal Chemistry, presenting exciting medicinal chemistry case studies from industry and academia. The program is designed together with the Division's NextGenMedChem group.

MedChemCASES #4

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

4:00 p.m. (Berlin time)
The seminar is free of charge, but REGISTRATION is needed.

"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 discover drugs 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: Innovation Award 2020
October 28, 2020
4:00 p.m. (Berlin time)

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.

The 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 independent scientific research of young scientists in the areas of medicinal and pharmaceutical chemistry.

MedChemCASES #2

Prof. Dr. Ed Tate (Imperial College London and Francis Crick Institute)
September 2, 2020
4:00 p.m. (Berlin time)

“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

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

“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.

zuletzt geändert am: 23.11.2020 17:13 Uhr von C.Kniep