Alford Joshua S, Lampe John W, Brach Dorothy, Chesworth Richard, Cosmopoulos Kat, Duncan Kenneth W, Eckley Sean T, Kutok Jeffrey L, Raimondi Alejandra, Riera Thomas V, Shook Brian, Tang Cuyue, Totman Jennifer, Farrow Neil A
Epizyme Inc., 50 Hampshire Street, Sixth Floor, Cambridge, Massachusetts 02139, United States.
ACS Med Chem Lett. 2022 Jun 7;13(7):1137-1143. doi: 10.1021/acsmedchemlett.2c00167. eCollection 2022 Jul 14.
SETD2, a lysine -methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that features a t(4,14) translocation. We recently reported the discovery of a novel small-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.
SETD2是一种赖氨酸甲基转移酶，是一种组蛋白甲基转移酶，在各种细胞过程中发挥重要作用，并被确定为具有t(4,14)易位特征的多发性骨髓瘤中的一个感兴趣靶点。我们最近报道了一种适用于临床前研究的新型小分子SETD2抑制剂工具化合物的发现。在此，我们描述了高级化学先导物的构象设计驱动的进化，这产生了适合临床评估的化合物。对该化学系列的进一步优化导致了EZM0414的发现，它是一种强效、选择性且口服生物可利用的SETD2抑制剂，在小鼠异种移植模型中具有良好的药代动力学特性和强大的药效学活性。
