Abstract ND12: Discovery and First Structural Disclosure of EZM0414: A potent and selective small molecule inhibitor of the histone methyltransferase SETD2

Abstract

Abstract SETD2 is the only known histone methyltransferase (HMT) capable of catalyzing H3K36 trimethylation (H3K36me3). It plays a critical role in several biological processes such as DNA damage repair and B cell development. Dysregulation in H3K36 methylation can occur in B cell malignancies, including multiple myeloma (MM) and diffuse large B cell lymphoma (DLBCL), often as a result of mutational events incurred during normal B cell development. For example, 15%-20% of MM patients harbor the high risk (4;14) chromosomal translocation (t), resulting in high expression of the multiple myeloma SET domain (MMSET) gene. MMSET (also known as NSD2) is an HMT that catalyzes H3K36me1 and H3K36me2 formation, which leads to increased levels of H3K36me2 in t(4;14) MM patients. Because H3K36me2 is the substrate of SETD2, we hypothesized that inhibiting SETD2 could target the underlying oncogenic mechanism driven by the dysregulated H3K36 methylation from MMSET overexpression in t(4;14) MM patients, and would establish proof of concept in this and other B cell malignancies (e.g. DLBCL) that may demonstrate dysregulated H3K36me3 or a dependency on SETD2. In this presentation, we will describe the discovery and structure of our clinical candidate EZM0414, a first-in-class, potent, selective, orally bioavailable small molecule inhibitor of the enzymatic activity of SETD2; robust anti-tumor effects of SETD2 inhibition with EZM0414 in MM (including t(4;14) MM) and DLBCL preclinical studies; and the outline of the ongoing first-in-human Ph1/1b open-label, multicenter study of EZM0414 in patients with relapsed/refractory MM or DLBCL. Citation Format: Jeffery L. Kutok. Discovery and First Structural Disclosure of EZM0414: A potent and selective small molecule inhibitor of the histone methyltransferase SETD2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND12.