MK-8242

In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS-3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for cancer therapy, including the identification of hit compounds, hit-to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed.

To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors.

MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 ( PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response.

Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 μM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure ( R2= 0.68; P < .001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days.

At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.