Feng Yangbo, Park HaJeung, Bauer Luke, Ryu Jae Cheon, Yoon Sung Ok
Reaction Biology Corporation, One Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
Crystallography Core Facility, Scripps Florida, TSRI, 130 Scripps Way, Jupiter, Florida 33458, United States.
ACS Med Chem Lett. 2020 Dec 13;12(1):24-29. doi: 10.1021/acsmedchemlett.0c00533. eCollection 2021 Jan 14.
Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor was a potent and isoform selective JNK3 inhibitor (IC = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome ( = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds and in human JNK3 were solved at 1.84 Å, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.
强效JNK3亚型选择性抑制剂是基于噻吩基-吡唑并脲骨架开发的。通过利用酶促和基于细胞的测定进行构效关系（SAR）研究，以及体外和体内药物代谢及药代动力学（DMPK）研究，开发出了具有口服生物利用度和脑渗透能力的强效且高度选择性的JNK3抑制剂。抑制剂是一种强效且亚型选择性的JNK3抑制剂（IC = 35 nM），在对374种野生型激酶的面板分析中仅对JNK3有显著抑制作用，在基于细胞的功能测定中具有高效力，在人肝微粒体中具有高稳定性（ = 66分钟）且CYP - 450抑制谱清晰，并且具有口服生物利用度和脑渗透性。此外，化合物和在人JNK3中的共晶体结构在1.84 Å分辨率下得到解析，结果表明这些JNK3亚型选择性抑制剂与ATP口袋结合，在疏水口袋 - I和疏水口袋 - II中均有相互作用。
