East Amanda, Polasek Callista G, Miller Elizabeth A, Ranganathan Srirajkumar, Reda Isabella D, Patel Aisha, Ahlers Christopher D, Zingales Sarah K, Karver Caitlin E
Department of Chemistry, DePaul University, Chicago, Illinois, USA.
United States Coast Guard Academy, New London, Connecticut, USA.
Chem Biol Drug Des. 2024 Dec;104(6):e70031. doi: 10.1111/cbdd.70031.
Caspase-1 is a sought-after therapeutic target for inflammatory conditions due to its role in activation and release of pro-inflammatory cytokines, but there has been little success getting drugs into the clinic. We have previously shown triaminopyrimidines such as CK-1-41 are potent, reversible small molecule inhibitors of caspase-1, likely binding in an allosteric site within the enzyme. A series of analogs of CK-1-41 were synthesized and tested against caspase-1 to develop a more robust structure-activity relationship profile. In general, alkyl and aryl groups were well tolerated via an ethylene or methylene linkage to the piperazine nitrogen, with IC values ranging from 13 to 200 nM. The most potent compounds were methylene linked o-tolyl (AE-2-21) and ethylene linked 4-trifluoromethylphenyl (AE-2-48) with IC values of 18 and 13 nM, respectively. Derivatives with electrophilic covalent warheads linked via an amide bond to the piperazine nitrogen were synthesized and characterized. CA-1-11 and EM-1-10 were semi-reversible, non-competitive inhibitors of caspase-1 with slightly reduced potencies of 134 and 144 nM, respectively. All derivatives docked well into the allosteric site, supporting our hypothesis that this family of caspase-1 inhibitors function via an allosteric non-competitive mechanism of inhibition.
半胱天冬酶 -1因其在促炎细胞因子的激活和释放中的作用，成为炎症性疾病备受关注的治疗靶点，但将药物推向临床的成效甚微。我们之前已表明，诸如CK -1-41之类的三氨基嘧啶是半胱天冬酶 -1的强效、可逆小分子抑制剂，可能结合于该酶的变构位点。合成了一系列CK -1-41的类似物，并针对半胱天冬酶 -1进行测试，以建立更完善的构效关系图谱。一般来说，烷基和芳基通过与哌嗪氮相连的亚乙基或亚甲基键连接时耐受性良好，IC值范围为13至200 nM。最有效的化合物是亚甲基连接的邻甲苯基（AE -2-21）和亚乙基连接的4-三氟甲基苯基（AE -2-48），IC值分别为18和13 nM。合成并表征了通过酰胺键与哌嗪氮相连的带有亲电共价弹头的衍生物。CA -1-11和EM -1-10是半胱天冬酶 -1的半可逆、非竞争性抑制剂，效力略有降低，分别为134和144 nM。所有衍生物均能很好地对接至变构位点，支持了我们的假设，即该家族的半胱天冬酶 -1抑制剂通过变构非竞争性抑制机制发挥作用。
