Ep212: Tim Shannon on Creating Targeted Protein Degraders as Medicines

What It Covers

Tim Shannon, general partner at Canaan Partners and former pulmonary physician, traces the development of targeted protein degraders from a 2013 lunch with Yale chemist Craig Crews through Arvinas's FDA approval and Halda Therapeutics's $3 billion acquisition by Johnson & Johnson, while introducing his third company, Quarry, focused on next-generation induced proximity pharmacology.

Key Questions Answered

• •Timing in biotech venture: Entering venture capital at the 2009 financial crisis trough, when peers demanded Phase 2 proof-of-concept before investing, proved optimal. Shannon's framework: identify when risk aversion has overcorrected and new science is maturing beneath depressed markets. The subsequent decade became one of biotech's strongest runs, rewarding those who committed capital when sentiment was most negative.
• •Oral bioavailability as a strategic inflection point: In Arvinas's second or third year, Shannon redirected roughly $10 million — a significant portion of the budget — exclusively toward solving oral bioavailability for PROTACs. Most competitors believed large bifunctional molecules couldn't be orally delivered. Resolving this transformed the company's product profile from a constrained IV/subcutaneous drug into a once-daily pill, unlocking broad commercial markets and validating the entire degrader field.
• •Phase 1 oncology as early proof strategy: When entering the value chain at discovery, design programs where meaningful signals appear in Phase 1, not Phase 2 or 3. Oncology enables this because patients are treated during dose escalation and tumor responses are measurable quickly. Arvinas targeted androgen receptor in prostate cancer and estrogen receptor in breast cancer specifically because PSA and tumor response data could validate the pharmacology early.
• •Biomarker-driven patient selection from ctDNA: Arvinas's AR degrader worked strongly in patients with AR point mutations but less so in wild-type AR patients. Circulating tumor DNA analysis revealed wild-type patients had acquired multiple co-driver pathways, making them AR-independent. The actionable lesson: use ctDNA profiling to stratify patients before enrollment, matching degrader therapy to tumors where the target protein remains the active driver.
• •RIPTACs and ternary complex binding affinity: RIPTACs (Receptor-Induced Proximity Targeted Chimeras) work by forcing a tissue-specific protein like the androgen receptor to bind an essential pan-cellular protein like BRD4. Binary drug-protein interactions involve roughly six atomic contacts; ternary complexes generate hundreds, producing picomolar binding affinity comparable to antibodies. BRD4, sequestered in the complex, cannot perform its transcriptional function, triggering apoptosis regardless of what other mutations are driving the tumor.
• •Stealth mode as a competitive and fundraising strategy: Halda raised approximately $125–150 million across private rounds without broad outreach, relying on Craig Crews's track record to attract select investors quietly. Presenting 30-patient Phase 1 data at ESMO 2024 publicly for the first time, after pre-briefing interested acquirers, generated competitive acquisition offers within weeks. The approach preserved negotiating leverage and prevented competitors from tracking the program's direction during development.