8:00 am

Registration & Networking Coffee

8:50 am Chair’s Opening Remarks

Delivering on the Vision of Drugging the Undruggable RAS Oncogene

9:00 am Combination Approaches to the Use of G12C KRAS Inhibitors

Synopsis

• KRAS G12C inhibitors have proved effective on many G12C KRAS mutant tumour in vitro, in vivo and in clinical trials, but acquired and pre-existing resistance is a problem

• Several approaches have been taken to establish how best to combine these drugs for more effective treatment of KRAS G12C mutant cancers and minimisation of resistance

• The response of KRAS G12C mutant lung tumour with these inhibitors profoundly alters the tumour immune microenvironment, allowing ingression of various effector immune cells: studying the phenotype of these cells suggests optimal combinations between KRAS G12C inhibitors and immunotherapies

9:30 am Targeting KRAS-Driven Oncogenic Signaling

  • Dwight Nissley Director, Cancer Research Technology Program; NCI RAS Initiative , Frederick National Laboratory for Cancer Research

Synopsis

• Inhibition of KRAS using small molecule inhibitors

• KRAS and activation of signaling at the plasma membrane

• KRAS complexes

10:00 am Drugging the Other KRAS Mutants

  • Darryl McConnell Senior Vice President & Research Site Head Austria , Boehringer Ingelheim

Synopsis

• Boehringer Ingelheim is taking a systematic approach to discovering drugs for all KRAS mutants

• The potential approaches to drugging KRAS beyond G12C with small molecules will be discussed

• Highlights from some of Boehringer Ingelheim’s KRAS programs will be presented

Optimising Robust Strategies to Target the Cancer Master Oncogene

10:40 am

Speed Networking & Morning Refreshments

11:30 am Targeting KRAS Singling

  • Mariano Barbacid AXA.CNIO Professor of Molecular Oncology , CNIO (Spanish National Cancer Research Center)

Synopsis

• Description of a genetically engineered KRAS/TP53-driven mouse lung and pancreatic tumour models driven by the KRASG12C mutation

• Targeting the canonical MAPK pathway is unacceptable toxic: Genetic evidence

• RAF1 as a “non-toxic” key mediator of KRAS oncogenic signalling

12:00 pm RAS Protein Flexibility & How to Target Cryptic Pockets to Drug the Undruggable Master Oncogene

  • Laurent Debussche Vice President, Global Head Molecular Oncology Research Therapeutic Area , Sanofi R&D

Synopsis

• RAS is a very flexible protein without any apparent druggable pocket which has resisted three decades of efforts to drug it

• Cryptic or induced pockets can be identified in addition to so-called SII pocket

• DNA-encoded library approach is a powerful approach to drug cryptic pockets such as SII pocket

12:30 pm Strategies to Inhibit RAS-Driven Cancers

  • Steve Kelsey President, Research & Development , Revolution Medicines

Synopsis

• SHP2 inhibition • Combination strategies

• Tri-Complex small molecule inhibitors of the oncogenic, GTP-bound (ON) form of KRAS

1:00 pm

Networking Lunch

Accelerating Anti-RAS Drug Discovery Through New Tools & Technologies

2:00 pm Chemotype Evolution: Accelerating Drug Discovery for Challenging Targets

Synopsis

• Chemotype Evolution (CE) is a versatile technology that accelerates drug discovery for challenging targets

• Using this technology, Carmot has discovered novel covalent KRASG12C inhibitors

• Covalent CE can be leveraged to identify new treatments for KRAS-driven cancers

2:30 pm Revealing New RAS Vulnerabilities with Protein Interference (PROTEINi)

Synopsis

• Oncogenic RAS remains largely undrugged

• PROTEINi identifies new targets which are synthetic lethal with RAS

• PhoreMost’s SITESEEKER platform provides key pharmacophoric information about how to go about drugging these targets

3:00 pm Design of Small Molecule Allosteric Inhibitors of KRAS

  • Juan Perez Chief Scientific Officer, Allinky Biopharma

Synopsis

• We will present the in vitro and in vivo results of a series of orally available small molecules that were designed following an in silico approach

• These novel therapeutics bind onto an allosteric site of KRAS

3:30 pm

Afternoon Refreshments & Poster Session

Empowering Potent Anti-RAS Drug Discovery with Novel Assays & Strategies

4:00 pm Targeting the Lymph Nodes to Enhance Mutant KRAS-Specific Vaccine Responses

  • Peter DeMuth Vice President of Research , Elicio Therapeutics

Synopsis

• Review of Elicio’s lymph node targeting AMP vaccination platform

• Data showing vaccine-induction of potent mKRAS-specific T cell responses

• Review of Elicio mKRAS clinical development program

4:30 pm Generation & Characterization of Antibodies Targeting Mutant KRAS Proteins

Synopsis

• Generation of selective antibodies

• Biochemical characterization

• Functional characterization in wild type and mutant cancer cell lines

5:00 pm Rush or Crash – “High” Ways or Dead Ends to Tackle RAS

  • Bert Klebl Managing Director & Chief Scientific Officer , Lead Discovery Center

Synopsis

Small molecule RAS modulation:

• Ras shuttling from endomembranes to the plasma membrane

• KRAS stabilisation

• KRAS wild type vs. mutant inhibition

5:30 pm A Subset of Flavaglines Inhibit KRAS Oncogene Activation

  • Krishnaraj Rajalingam Heisenberg Professor of Cell Biology, Cell Biology Unit , University Medical Center Mainz

Synopsis

• Novel assays to measure KRAS activation in cells

• Identification of flavagline derivatives as potent KRAS inhibitors

• Mechanisms and in vivo effects

6:00 pm

Chair’s Closing Remarks & End of Day One