Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, 602 00 Brno, Czech Republic.
J Med Chem. 2022 Apr 14;65(7):5701-5723. doi: 10.1021/acs.jmedchem.1c02228. Epub 2022 Mar 18.
Histone methyltransferase DOT1L is an attractive therapeutic target for the treatment of hematological malignancies. Here, we report the design, synthesis, and profiling of new DOT1L inhibitors based on nonroutine carbocyclic C-nucleoside scaffolds. The experimentally observed SAR was found to be nontrivial as seemingly minor changes of individual substituents resulted in significant changes in the affinity to DOT1L. Molecular modeling suggested that these trends could be related to significant conformational changes of the protein upon interaction with the inhibitors. The compounds and (-)- (), carbocyclic C-nucleoside analogues of the natural nucleoside derivative , and the clinical candidate (pinometostat) potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compound was found to be more metabolically stable and significantly less toxic in vivo than pinometostat itself.
组蛋白甲基转移酶 DOT1L 是治疗血液系统恶性肿瘤的一个有吸引力的治疗靶点。在这里，我们报告了基于非常规碳环 C-核苷支架的新型 DOT1L 抑制剂的设计、合成和分析。实验观察到的 SAR 是非平凡的，因为单个取代基的微小变化会导致与 DOT1L 的亲和力发生显著变化。分子模拟表明，这些趋势可能与抑制剂相互作用时蛋白质的显著构象变化有关。化合物 和 (-)-()，天然核苷衍生物 的碳环 C-核苷类似物，以及临床候选药物 （pinometostat），在体外和细胞内均能有效且选择性地抑制 DOT1L。最有效的化合物 被发现比 pinometostat 本身在体内更稳定，毒性更小。
