MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration

MDM2 is a key negative regulator of the tumor suppressor p53 and
an attractive target for cancer therapy. We report the discovery of
MD-4251, the first orally efficacious MDM2 degrader developed using
PROTAC technology. MD-4251 induces potent and rapid MDM2 degradation
in RS4;11 cells (DC50 = 0.2 nM; Dmax = 96% at 2 h), leading to robust p53 activation. It selectively
inhibits the growth of acute leukemia cell lines with wild-type p53,
with minimal activity in p53 mutant lines. MD-4251 shows excellent
oral bioavailability in mice, favorable metabolic stability, and no
CYP or hERG liabilities. A single oral dose induces sustained MDM2
depletion and attains complete tumor regression in vivo. These results
support MD-4251 as a promising therapeutic candidate for cancers through
depletion of MDM2.