Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA.
Translational Core Laboratory, University of Maryland Greenebaum Cancer Center, 655 W Baltimore Street, Baltimore, MD, 21201, USA.
Eur J Med Chem. 2019 Oct 15;180:449-456. doi: 10.1016/j.ejmech.2019.06.089. Epub 2019 Jun 29.
Rho-associated protein kinases (ROCKs) are ubiquitously expressed in most adult tissues, and are involved in modulating the cytoskeleton, protein synthesis and degradation pathways, synaptic function, and autophagy to list a few. A few ROCK inhibitors, such as fasudil and netarsudil, are approved for clinical use. Here we present a new ROCK inhibitor, boronic acid containing HSD1590, which is more potent than netarsudil at binding to or inhibiting ROCK enzymatic activities. This compound exhibits single digit nanomolar binding to ROCK (Kds < 2 nM) and subnanomolar enzymatic inhibition profile (ROCK2 IC50 is 0.5 nM for HSD1590. Netarsudil, an FDA-approved drug, inhibited ROCK2 with IC50 = 11 nM under similar conditions). Whereas netarsudil was cytotoxic to breast cancer cell line, MDA-MB-231 (greater than 80% growth inhibition at concentrations greater than 5 μM), HSD1590 displayed low cytotoxicity to MDA-MB-231. Interestingly, at 1 μM HSD1590 inhibited the migration of MDA-MB-231 whereas netarsudil did not.
Rho 相关蛋白激酶（ROCKs）广泛存在于大多数成年组织中，参与调节细胞骨架、蛋白质合成和降解途径、突触功能和自噬等过程。几种 ROCK 抑制剂，如法舒地尔和那他珠单抗，已被批准用于临床。在这里，我们介绍了一种新的 ROCK 抑制剂，含有硼酸的 HSD1590，它与 ROCK 的结合或抑制 ROCK 酶活性的能力比那他珠单抗更强。该化合物对 ROCK 的结合具有个位数纳摩尔亲和力（Kd 值<2 nM），酶抑制活性呈亚纳摩尔水平（HSD1590 对 ROCK2 的 IC50 为 0.5 nM。法舒地尔，一种已被 FDA 批准的药物，在类似条件下对 ROCK2 的抑制 IC50 值为 11 nM）。虽然那他珠单抗对乳腺癌细胞系 MDA-MB-231 具有细胞毒性（浓度大于 5 μM 时，超过 80%的生长抑制），但 HSD1590 对 MDA-MB-231 的细胞毒性较低。有趣的是，在 1 μM 时，HSD1590 抑制了 MDA-MB-231 的迁移，而那他珠单抗则没有。
