Advanced
Emerging
Sule Karaman, PhD, DABT
Associate Director
Novartis
Cambridge, Massachusetts, United States
Ruth Roberts, PhD, ERT, FBTS, ATS, FRSB, FRCPath
Director and Cofounder
ApconiX
Macclesfield, England, United Kingdom
Lyn Jones, PhD, FAAAS, FRSC, FRSB, FLS, FRSPH
Principal Investigator and Director
Center for Protein Degradation, Jones Lab
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Xiaoting Wang, PhD, DABT
Director
Translational Safety & Bioanalytical Sciences
Amgen Inc.
South San Francisco, California, United States
Brandon Jeffy, PhD, DABT
Senior Director
Nonclinical Safety and Toxicology
Crinetics Pharmaceuticals
San Diego, California, United States
Katie Stamp, PhD
Senior Director, Toxicology
Nonclinical Safety
Bristol Myers Squibb
New Brunswick, New Jersey, United States
Ronald Wange, PhD
Associate Director for Pharmacology and Toxicology
CDER
US Food and Drug Administration, Center for Drug Evaluation and Research
Silver Spring, Maryland, United States
Targeted protein degraders (TPDs) are rapidly evolving classes of drugs with great promise to address difficult drug targets in oncologic and non-oncologic disease. However, there is limited scientific consensus on the application of rigorous, consistent, and effective methods for assessment of their clinical safety. TPDs, including molecular glues and heterobifunctional degraders, use endogenous protein degradation processes to target previously ‘undruggable’ sites and diverse therapeutic protein targets. The goal of this session is to discuss the nonclinical and translational safety assessment of heterobifunctional degraders (often called proteolysis targeting chimeras or PROTACS) and molecular glues, focusing on the key challenges of early de-risking, nonclinical species selection and clinical translation. The first speaker will provide an introduction as well as discuss approaches to TPD safety assessments, illustrated by functional genomic profiling of molecular glues and PROTACs. The second speaker will address early de-risking strategies, focusing on a novel proteomic platform to identify off-target proteins. The third speaker will discuss strategies for assessing TPD safety in drug discovery, including the discussion of in vitro assays to inform in vivo studies. The fourth speaker will address the challenge of selecting pharmacologically relevant species to address the toxicity of TPDs, and will present some case studies. Our final speaker will present the regulatory perspective on the challenges and opportunities of protein degradation therapies. Overall, this course will address TPD safety assessment and how approaches may differ from those used for ‘traditional’ small molecule development.
Symposium Chair: Sule Karaman, PhD, DABT – Novartis
Symposium Speaker: Lyn Jones, PhD, FAAAS, FRSC, FRSB, FLS, FRSPH – Dana-Farber Cancer Institute
Symposium Speaker: Xiaoting Wang, PhD, DABT – Amgen Inc.
Symposium Speaker: Brandon D. Jeffy, PhD, DABT – Crinetics Pharmaceuticals
Symposium Speaker: Katie Stamp, PhD – Bristol Myers Squibb
Symposium Speaker: Ronald L. Wange, PhD – US Food and Drug Administration, Center for Drug Evaluation and Research