D16-M1P2 is a potent, highly specific, bifunctional PKMYT1-targeting PROTAC degrader with DC50 of 0.7 nM and Dmax of 90% in HCC1569 cells.
D16-M1P2 inhibits pCDK1 (T14) in HCC1569 cells with IC50 of 9.0 nM.
D16-M1P2 (100 M) caused rapid PKMYT1 degradation, reducing PKMYT1 levels by over 80% within 4 hours and reaching maximal degradation at 24 hours.
D16-M1P2 time-dependently inhibited pCDK1 (T14), achieving over 50% inhibition after 4 hours of treatment at 100 nM.
D16-M1P2 demonstrates dual degradation and inhibition for PKMYT1, shows PKMYT1 enzymatic inhibition (IC50=7.6nM) and intracellular target engagement (EC50=12.0 nM).
D16-M1P2 exhibits high specificity for PKMYT1 with over 50-fold selectivity over only 3 kinases (BRAF, RAF1, and SRC) in 403 kinases panel.
D16-M1P2 inhibits the growth of tumors with CCNE1 amplification or deleterious alterations in FBXW7/PPP2R1A (IC50=177 nM), 12-fold greater selectivity over wild-type cells.
D16-M1P2 exhibited dose-dependent tumor growth inhibition, achieving 35.1% and 66.4% inhibition at 40 mg/kg and 120 mg/kg dosed twice daily for 21 days in NOD/SCID mice with subcutaneous CCNE1-amplified HCC1569 tumors, induced dose-dependent PKMYT1 degradation and corresponding pCDK1 (T14) inhibition with favorable plasma exposure.