Problem

Although cyclin dependent kinase 9 (CDK9) is a promising drug target, traditional small-molecule inhibitors face challenges due to CDK9's structural similarities with other kinases, leading to off-target effects and limited efficacy

Solution

• Researchers from The Ohio State University and University of Cincinnati have developed bifunctional CDK9-targeting degraders combining a CDK9-binding moiety and an E3 ligase recruiter (e.g., thalidomide derivatives) linked by tunable connectors. The heterobifunctional small molecules engage both target proteins facilitating ubiquitination of CDK9 and subsequent degradation by the proteasome
• The optimized PROTAC degraders have increased solubility, potency and ability to engage undruggable targets with improved selectivity and reduced side effects in treating hematologic malignancies like acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)
• CDK9 degraders showed nanomolar cytotoxicity in MV411 leukemia cells in vitro, CDK9 degradation via Western blot, and in vivo tumor reduction in xenograft models
• Optimized linkers enhance solubility and potency while mitigating the liver toxicity observed in early studies

Applications

Cancer therapy for hematological malignancies: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and potential therapeutic treatment for other non-solid and solid tumors

Advantages

• The selective bifunctional CDK9 degraders engage both target proteins, disrupt both enzymatic and scaffolding functions of target proteins, and enable catalytic degradation at low doses while still achieving the desired pharmacological effects
• The optimized bifunctional CDK9 degraders show favorable solubility, selectivity and drug properties

Seeking opportunities for out-licensing or collaboration