CHAPTER 11: Discovery of AMG 232, a Small Molecule MDM2 Inhibitor in Clinical Development and its Back-up Clinical Candidate, AM-7209

Significant drug discovery efforts have been poured into the design of selective small molecule inhibitors of the MDM2–p53 protein–protein interaction since the first co-crystal structure of the p53 peptide bound to MDM2 was reported in 1996. As a result, several compounds have been advanced into human clinical trials for the treatment of cancers in the past decade. Amgen's structure-based rational design and extensive structure–activity relationship studies led to the discovery of AMG 232, a novel piperidinone series small molecule inhibitor of the MDM2–p53 protein–protein interaction, which is currently in Phase I and II clinical trials for multiple tumor indications. AMG 232 is a potent MDM2 inhibitor (SPR K_d = 0.045 nM, SJSA-1 EdU IC₅₀ = 9.1 nM) with remarkable pharmacokinetic properties. AMG 232 has demonstrated in vivo antitumor activity in several tumor xenograft models and led to complete tumor regression of MDM2 amplified SJSA-1 tumors (ED₅₀ = 9.1 mg kg⁻¹, QD dosing). This chapter covers a comprehensive discovery story of AMG232 from the de novo design of a rigid novel piperidinone scaffold to the systemic optimization of the piperidinone scaffold towards AMG 232 and its back-up clinical candidate AM-7209.