从 PROTAC 到抑制剂：基于结构的强效和口服生物可利用 BET 抑制剂的发现。
From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors.
机构信息
University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221, Belgrade, Serbia.
Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
出版信息
Eur J Med Chem. 2023 May 5;251:115246. doi: 10.1016/j.ejmech.2023.115246. Epub 2023 Mar 4.
An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.
基于 CLICK 化学的 BET PROTAC 与 BRD2（BD2）结合的 X 射线结构，激发了 JQ1 衍生的杂环酰胺的合成。这项工作导致发现了与 JQ1 和 birabresib 相比具有整体改善的特性的强效 BET 抑制剂。噻二唑衍生的 1q（SJ1461）对 BRD4 和 BRD2 具有优异的亲和力和在急性白血病和髓母细胞瘤细胞系中的高活性。与 BRD4-BD1 共结晶的 1q 的结构显示与 AZ/BC 环的极性相互作用，特别是与 Asn140 和 Tyr139，合理化了观察到的亲和力提高。此外，对该类化合物的药代动力学性质的探索表明，杂环酰胺部分改善了药物样特征。我们的研究导致发现了强效、可口服生物利用的 BET 抑制剂 1q（SJ1461），作为进一步开发的有前途的候选药物。
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