Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, California 92521, United States.
J Med Chem. 2021 Nov 11;64(21):16147-16158. doi: 10.1021/acs.jmedchem.1c01459. Epub 2021 Oct 27.
We have recently reported on Lys-covalent agents that, based on aryl-sulfonyl fluorides, were designed to target binding site Lys 311 in the X-linked inhibitor of apoptosis protein (XIAP). Similar to XIAP, melanoma-IAP (ML-IAP), a less well-characterized IAP family protein, also presents a lysine residue (Lys 135), which is in a position equivalent to that of Lys 311 of XIAP. On the contrary, two other members of the IAP family, namely, cellular-IAPs (cIAP1 and cIAP2), present a glutamic acid residue in that position. Hence, in the present work, we describe the derivation and characterization of the very first potent ML-IAP Lys-covalent inhibitor with cellular activity. The agent can be used as a pharmacological tool to further validate ML-IAP as a drug target and eventually for the development of ML-IAP-targeted therapeutics.
我们最近报道了基于芳基磺酰氟的 Lys 共价试剂，该试剂旨在针对凋亡蛋白抑制因子（XIAP）中的结合位点 Lys311。与 XIAP 相似，黑色素瘤 IAP（ML-IAP）是一种特征不太明确的 IAP 家族蛋白，也存在一个赖氨酸残基（Lys135），其位置相当于 XIAP 中 Lys311 的位置。相反，IAP 家族的另外两个成员，即细胞 IAPs（cIAP1 和 cIAP2），在该位置存在一个谷氨酸残基。因此，在本工作中，我们描述了首个具有细胞活性的强效 ML-IAP Lys 共价抑制剂的衍生和表征。该试剂可用作药理学工具，以进一步验证 ML-IAP 作为药物靶标，并最终用于开发针对 ML-IAP 的治疗方法。
