Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression

Abstract

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, non-peptide 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 IC 50 value of 1.5 nM in inhibition of growth of RS4;11 cells and also low nanomolar IC 50 values in a panel of acute 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.

The hydrophobically-tagged MDM2–p53 interaction inhibitor Nutlin-3a-HT is more potent against tumor cells than Nutlin-3a

“…In a recent study on MDM2-targeting PROTACs based on the MDM2-p53 interaction inhibitor MI-1061 and cereblon ligands, a similar effect was observed for some of the PROTACS. 21 Consistent with the results of the Western blots, HCT-116 cells treated with 2 showed a higher degree of apoptosis than cells treated with 1 did (39 AE 7% apoptotic cells for 30 mM 2 vs. 15 AE 1% for 30 mM 1, Fig. 5A and Fig.…”

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…Currently, several other drug discovery strategies have also been attempted, including modulating MDM2's E3 ubiquitin ligase activity, inducing MDM2 autoubiquitination, inhibiting the MDM2/MDMX interaction, blocking MDM2 gene expression, and MDM2 degraders based on the proteolysis targeting chimera concept . However, MDM2 has been shown to exert pathogenic effects through both p53‐dependent and p53‐independent mechanisms.…”

Cereblon vs VHL: Hijacking E3 Ligases Against Each Other Using PROTACs

“…It is noteworthy that a recent study reported MDM2 PROTAC degraders, designed by linking an MDM2 inhibitor via either a thalidomide-based CRBN ligand or a VHL ligand. 57 Potent and selective PROTAC-induced degradation of MDM2 was observed for the CRBN-MDM2 heterodimers. However notably, protein level of the hijacked CRBN or VHL ligases were not monitored.…”

“…However notably, protein level of the hijacked CRBN or VHL ligases were not monitored. 57 Future work is warranted to interrogate many more combinations of E3 ligases and hetero-dimerizer compounds to bring them together. Given the number of E3 ligases predicted to function in cells (up to 600) this approach could speed up our ability to chemically intervene on E3 ligase themselves using targeted protein degradation, with both biological and therapeutic benefits.…”