Cambridge Healthtech Institute’s Inaugural

Small G Proteins

Targeting Ras, Other Small GTPases and Their Molecular Partners

September 16 - 17, 2020 ALL TIMES EDT

Small G proteins are a superfamily of intracellular enzymes with similar core structures that hydrolyze GTP molecules and play roles important to cell growth and other core cellular processes. The most ‘famous’ small G protein subfamily, Ras proteins, has been known for decades to contribute to the growth of many types of cancerous cells when Ras is stuck in its ‘ON’, GTP-bound state. Yet, drug discovery efforts to find small molecule drugs to turn Ras ‘off’ have been difficult because it’s part of difficult-to-drug molecular complexes. Thanks to new biophysical approaches, there are a few anti-Ras compounds in early-stage clinical trials and the field of targeting small G protein regulatory complexes has been rejuvenated. Join CHI’s Inaugural Small G Proteins conference to hear from drug discovery chemists, biologists, and pharmacologists working on ‘Ras’ and other small G protein-related projects.

Wednesday, September 16

KRAS-TARGETED COMPOUNDS

Dirk Kessler, PhD, Scientific Director, Medicinal Chemistry/SR , Boehringer Ingelheim

Many biological processes are controlled via Protein-protein interactions often lacking deep druggable pockets. KRAS, the most common oncogenic driver in human cancers is also primarily controlled through such protein contacts with still no approved drug directly targeting RAS or inhibiting important interactions to other direct binding partners such as cRAF or SOS1. The identification of the two chemicals probes BI-2852 (KRAS) as well as BI-3406 (SOS1) will be presented in more detail highlighting the learnings for such difficult PPI targets and the impact of structural data for the design process.

9:50 am

On the Road to AMG-510, a First-in-Human Covalent Inhibitor of KRAS G12C: High-throughput Mass Spectrometric Analysis of Covalent Protein-Inhibitor Adducts

John D. McCarter, PhD, Principal Scientist, Discovery Technologies, Amgen, Inc.

 

A high-throughput MS platform was used to accurately detect and quantitate different covalent modifications of proteins, including KRAS G12C, which contain one or more reactive cysteines, lysines, or other nucleophilic residues. We employed the Agilent RapidFire system to rapidly quantitate the extent of covalent protein-inhibitor adduct formation by MS for several proteins, including KRAS G12C. We used this approach to screen large numbers of potential covalent inhibitors in an automated fashion and to test medicinal chemistry compounds as part of a regular lead optimization cycle for KRAS G12C leading to the development of AMG-510.

 

10:10 am The Anti-Tumor Activity of the KRAS G12C Inhibitor MRTX849 and Potential for Therapeutic Improvement with Rational Combination Strategies
Jill F. Hallin, Principal Scientist, Mirati Therapeutics, Inc.

We examined the utility of MRTX849, a covalent KRAS G12C inhibitor, in treating KRASG12C mutated cancers and comprehensively profiled sensitive and partially resistant preclinical models. We identified mechanisms likely responsible for limiting the single agent activity of MRTX849 in partially resistant KRASG12C-dependent models and identified clinically actionable combination strategies to augment MRTX849 in NSCLC and CRC patient populations.

10:30 am Session Break
10:50 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Daniel A. Erlanson, PhD, Vice President, Chemistry, Frontier Medicines Corp.
Panelists:
Dirk Kessler, PhD, Scientific Director, Medicinal Chemistry/SR , Boehringer Ingelheim
John D. McCarter, PhD, Principal Scientist, Discovery Technologies, Amgen, Inc.
Jill F. Hallin, Principal Scientist, Mirati Therapeutics, Inc.
11:10 am Coffee Break - View Our Virtual Exhibit Hall

PAN RAS INHIBITORS

11:25 am

Targeting Ras with Novel Drug Discovery Efforts at the NCI RAS Initiative

Dominic Esposito, PhD, Director, Protein Sciences, Frederick National Laboratory

The NCI RAS Initiative, led by scientific director, Frank McCormick of UCSF, combines novel drug discovery approaches (covalent tethering, computational modeling, and structure-guided fragment-based screening) to identify new compounds that directly target KRAS and its oncogenic mutants. These techniques provide a potential set of new targets in RAS drug discovery which have not yet been fully explored and will be discussed in this presentation.

11:45 am

RAS Inhibitor, ANC 007, Potently and Selectively Kills Cancer Cells Harboring Activated RAS

Gary A. Piazza, PhD, Professor, Pharmacology, University of South Alabama

An iterative medicinal chemistry/screening campaign identified a novel group of indenes with unique chemical and biological selectivity to inhibit the growth of cancer cells harboring mutant RAS. Lead optimization resulted in ANC 007 with IC50 values in the low nanomolar range and selectivity indices >100 fold. ANC 007 inhibited the growth of a large panel of human cancer cell lines having the most prevalent RAS mutational codons of all three RAS isozymes. Cancer cells with activated RAS from mutations in receptor tyrosine kinases or NF1 were also sensitive, while cancer cells having low activated RAS levels or cells from normal tissues were essentially insensitive. The mechanism of action involves suppression of activated RAS levels and MAPK/AKT signaling followed by mitotic arrest and apoptosis. ANC 007 also decreased levels of activated RAS and MAPK signaling in vivo at dosages that suppressed tumor growth and were well-tolerated. Treatment of immunocompetent mice with ANC 007 also suppressed PD-L1 levels on cancer cells and activated antitumor immunity. Experiments with recombinant RAS show direct binding of ANC 007 to the protein by NMR spectroscopy, inhibition of GTP binding, and blockage of RAS-effector interactions.

12:05 pm Session Break
12:25 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Adrienne D. Cox, PhD, Professor, Radiation Oncology, Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill
Panelists:
Dominic Esposito, PhD, Director, Protein Sciences, Frederick National Laboratory
Gary A. Piazza, PhD, Professor, Pharmacology, University of South Alabama
John McGee, Associate Director & Scientific Founder, FogPharma
12:45 pm Lunch Break - View Our Virtual Exhibit Hall

GTPase STRUCTURAL INSIGHTS

1:15 pm

Griptides: High-Affinity Ras Binders that Remodel Its Effector Domain

John McGee, Associate Director & Scientific Founder, FogPharma

We share the discovery of scaffolded miniproteins (“Griptides”) that were engineered to bind the Ras proteins with picomolar affinity, and the subsequent characterization of their binding mode by solving high-resolution crystal structures. These structures reveal Ras trapped in a conformation that exposes a large binding pocket in the effector domain that connects two smaller pockets, which suggests that Ras may possess a surface pocket sufficiently large for effective small-molecule targeting.

1:35 pm

Small-Molecule Ral GTPase Targeted Covalent Inhibitors

Samy O. Meroueh, PhD, Associate Professor, Biochemistry & Molecular Biology, Indiana University

The development of K-Ras G12C covalent inhibitors has led to clinical candidates. The overwhelming majority of Ras mutants and all Ral proteins do not have an accessible cysteine. We report one compound class that forms a covalent bond with non-catalytic residue Tyr-82. High-resolution crystal structures at 1.2-Å resolution revealed a deep, hydrophobic and druggable pocket, suggesting that it could be used to develop therapeutics targeting oncogenic Ras lacking cysteine.

1:55 pm Refresh Break - View our Exhibit Hall
3:00 pm Interactive Breakout Discussions - View Our Virtual Exhibit Hall

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Discussion topics and moderators will be listed on the website.

3:35 pm Close of Day

Thursday, September 17

SMALL G PROTEINS: STRUCTURE & PARTNERS

10:35 am

KRAS4A Directly Regulates Hexokinase Creating a Metabolic Vulnerability for KRAS-Driven Cancer

Mark R. Philips, MD, Professor, New York University Grossman School of Medicine

The most frequently mutated oncogene in cancer is KRAS, which utilizes alternative fourth exons to generate two gene products, KRAS4A and KRAS4B, that differ only in their C-terminal membrane-targeting region. Because oncogenic mutations occur in exons 2 or 3, when KRAS is activated by mutation two constitutively active KRAS proteins are encoded, each capable of transforming cells. No functional distinctions among the splice variants have been established. Oncogenic KRAS alters tumor metabolism. Among these alterations is increased glucose uptake and glycolysis, even in the presence of abundant oxygen (the Warburg Effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes, direct regulation of metabolic enzymes has not been examined. We report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, establishing HK1 as an effector of KRAS4A. The interaction is unique to KRAS4A because the palmitoylation/depalmitoylation cycle of this RAS isoform permits co-localization with HK1 on the outer mitochondrial membrane (OMM). In recent, unpublished work we have explored the effect of KRAS4A on multimerization of HK1 on the OMM as a mechanism for controlling allosteric regulation of the enzyme. KRAS4A expression in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.

10:55 am

Blocking Downstream Ras-Signaling

Adrienne D. Cox, PhD, Professor, Radiation Oncology, Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill
11:15 am Session Break
11:35 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Matthew A. Marx, PhD, Vice President, Drug Discovery, Mirati Therapeutics, Inc.
Panelists:
Samy O. Meroueh, PhD, Associate Professor, Biochemistry & Molecular Biology, Indiana University
Mark R. Philips, MD, Professor, New York University Grossman School of Medicine
Adrienne D. Cox, PhD, Professor, Radiation Oncology, Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill
11:55 am Coffee Break - View Our Virtual Exhibit Hall

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PANEL AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
  • Data Sciences
  • ​Novel Chemical Modalities
  • Investment and Partnering Models
  • COVID-19 Progress as Examples of Successful Partnerships
Panelists:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Stephen A. Hitchcock, PhD, Head, Research, Takeda Pharmaceuticals, Inc.
1:35 pm Lunch Break - View Our Virtual Exhibit Hall
2:05 pm Close of Small G Proteins Conference





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