Category: tetrahydroisoquinoline. The reaction of aromatic heterocyclic molecules with protons is called protonation. Aromatic heterocycles are more basic than benzene due to the participation of heteroatoms. Compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole, is researched, Molecular C18H11Cl2N3O2S, CAS is 882562-40-5, about Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma. Author is Jiang, Baishan; Jiang, Jie; Kaltheuner, Ines H.; Iniguez, Amanda Balboni; Anand, Kanchan; Ferguson, Fleur M.; Ficarro, Scott B.; Seong, Bo Kyung Alex; Greifenberg, Ann Katrin; Dust, Sofia; Kwiatkowski, Nicholas P.; Marto, Jarrod A.; Stegmaier, Kimberly; Zhang, Tinghu; Geyer, Matthias; Gray, Nathanael S..
Development of inhibitors targeting CDK12/13 is of increasing interest as a potential therapy for cancers as these compounds inhibit transcription of DNA damage response (DDR) genes. We previously described THZ531, a covalent inhibitor with selectivity for CDK12/13. In order to elucidate structure-activity relationship (SAR), we have undertaken a medicinal chem. campaign and established a focused library of THZ531 analogs. Among these analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in cancer cells. A 3.0 Å co-crystal structure with CDK12/CycK provides a structural rational for selective targeting of Cys1039 located in a C-terminal extension from the kinase domain. With moderate pharmacokinetic properties, BSJ-01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day, i.p. administration. Taken together, BSJ-01-175 represents the first selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date.
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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem