MD-224

Human murine double minute 2 (MDM2) protein is a primary endogenous cellular inhibitor of the tumor suppressor p53 and has been pursued as an attractive cancer therapeutic target. Several potent, nonpeptide, small-molecule inhibitors of MDM2 are currently in clinical development. In this paper, we report our design, synthesis, and evaluation of small-molecule MDM2 degraders based on the proteolysis targeting chimera (PROTAC) concept. The most promising compound (MD-224) effectively induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells. It achieves an IC₅₀ value of 1.5 nM in inhibition of growth of RS4;11 cells and also low nanomolar IC₅₀ values in a panel of leukemia cell lines. MD-224 achieves complete and durable tumor regression in vivo in the RS4;11 xenograft tumor model in mice at well-tolerated dose schedules. MD-224 is thus a highly potent and efficacious MDM2 degrader and warrants extensive evaluations as a new class of anticancer agent.

Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematol. cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a mol. glue for the protein degradation of neosubstrates by CRL4CRBN.Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins.The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy.However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression.Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematol. cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide.PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity.PROTACs also exert anti-proliferative effects in all examined cell lines.Thus, 6-position-modified lenalidomide is a key mol. for selective TPD using thalidomide derivatives and PROTACs.