Lecture Notes: Paula Hammond and Angela Koehler

Introduction by Paula Hammond

• Introduction to the session featuring young scientists.
• Angela Koehler:
  • Associate Director of the Koch Institute.
  • Associate Professor of Biological Engineering at MIT.
  • Education: BSc from Reed College, PhD from Harvard University.
  • Formerly at Broad Institute, Director of Transcriptional Chemical Biology.
  • Key roles at Koch Institute since 2014.
  • Awards: Genome Technology Young Investigator, AACR Bayer Innovation Award, etc.
  • Entrepreneur: Founded Ligon Discovery, Kronos Bio, and 76Bio.
  • Serves on various scientific advisory boards and as a pre-health advisor at MIT.

Presentation by Angela Koehler

Overview

• Honored to be part of the future science lineup.
• Focus on modulating the oncoprotein MYC.

Disclosures

• Companies interested in MYC: Kronos, MS2 Array, etc.
• Founded 76Bio with Dane Wittrup.
• Role at the lab: Expanding the repertoire of un-druggable targets.
  • Develop technologies for challenging targets.
  • Goal: Find tools to clarify target relevance and industry interest.
  • Recent focus on nanomedicine and drug delivery.

MYC Oncoprotein Modulation

• Problem: MYC deregulation impacts all hallmarks of cancer.
  • Drives uncontrolled proliferation, tumor invasion, etc.
  • 70% of human tumors show MYC deregulation.
• Mechanism: MYC is a master regulator of gene transcription.
• Challenge: Hard to target due to biomolecular interactions and disordered nature.
• Strategy: Disrupt MYC-MAX interaction.
  • MYC interacts with MAX to regulate transcription.
  • MYC is like a piece of spaghetti that orders when it finds MAX.

Vignette 1: Chemical Probe Targeting MAX

• Rationale: Use high throughput screening to target MAX.
• Method:
  • Applied purified MAX to small molecule microarrays.
  • Assessed molecules in Myc-driven reporter gene assays.
  • Focused on a stabilizing molecule, KI-MS2-008.
• Findings:
  • KI-MS2-008 leads to MYC protein level reduction via proteasome-dependent process.
  • Mechanism: Shifts equilibrium from MYC-MAX heterodimers to MAX-MAX homodimers.

Vignette 2: CDK9 Inhibition

• Initial Goal: Identify binders for androgen receptor variants in prostate cancer.
  • Screened small molecule microarrays in cell lysates.
  • Found selective CDK9 inhibitor: KI-ARv-03/KI-ARv-04 rebranded as KB-0742 by Kronos Bio.
• Mechanism: CDK9 is involved in Myc regulation and transcription programs.
  • Myc regulates androgen receptor expression.
  • Found CDK9 inhibitor impacts phosphorylation and transcription.
• Clinical Development: Compound in Phase 1/2 clinical trials.
  • Targeting Myc-amplified tumors.
  • Early phase showing good safety and target engagement.

Future Directions

• Inspired by interactions with families affected by Myc-driven cancers.
• Focus on pediatric tumors and translational research.

Conclusion

• Acknowledgements: Lab trainees, collaborators, and funding sources.