pomalidomide

This finding highlights the functional relevance of IMiD's inherent polypharmacology in circumventing primary resistance mechanisms at the cellular level. Together, our results identify the ARID2-containing PBAF complex as a critical vulnerability in resistant myeloma cells and provide a mechanistic rationale for designing combination strategies that co-target this complex, with the potential to enhance therapeutic efficacy by overcoming drug resistance.

Triplet regimens that include an immunomodulatory agent, proteasome inhibitor, and dexamethasone are widely used in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM)...Additionally, we have compared these results with similar combinations with the immunomodulatory agent pomalidomide (POM). Our studies indicate that the MEZI/BTZ/DEX triplet is superior to all single agents and POM/BTZ/DEX in terms of potency of antiproliferative and proapoptotic activities, substrate degradation depth and kinetics in the presence of BTZ, and in vivo efficacy. We show that the combination of MEZI with BTZ increases cell death through disruption of multiple phases of the cell cycle and this thereby enhances the direct cytotoxic effects of the combination treatment.

P1/2, N=153, Recruiting, GlaxoSmithKline | Phase classification: P1 --> P1/2 | N=55 --> 153

P2, N=52, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Jun 2026 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

P3, N=915, Recruiting, Regeneron Pharmaceuticals | Not yet recruiting --> Recruiting

P1, N=62, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2028 --> Jan 2029 | Trial primary completion date: Jan 2026 --> Jan 2028

P1, N=33, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Jun 2026 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

P2, N=50, Recruiting, Massachusetts General Hospital | Not yet recruiting --> Recruiting | Trial completion date: Dec 2026 --> Dec 2030 | Trial primary completion date: Dec 2025 --> Dec 2028

P1, N=125, Recruiting, K36 Therapeutics, Inc. | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Dec 2025 --> Dec 2027

P3, N=944, Recruiting, Pfizer | Trial primary completion date: Dec 2025 --> Apr 2026

P3, N=810, Recruiting, Celgene | Trial primary completion date: Nov 2025 --> Jan 2027

The pomalidomide/thalidomide-based series (BP1-BP5) exhibited strong antiproliferative activity against leukemia and multiple myeloma cells, accompanied by degradation of CRBN neosubstrates. The hit compounds from both series, BP1 (DC50, 24 h = 20 nM, Dmax, 24 h = 99%) and BP6 (DC50, 24 h = 81 nM, Dmax, 24 h = 93%), demonstrated highly efficient and selective HDAC8 degradation. Pretreatment with BP6 enhanced the tumor suppressor p53 stability, thereby significantly increasing the sensitivity of leukemia cells to the MDM2 antagonist idasanutlin than PCI-34051, highlighting its unique potential for combinatorial therapy without impacting neosubstrates.