Kale Vijay Pralhad, Hengst Jeremy A, Sharma Arati K, Golla Upendarrao, Dovat Sinisa, Amin Shantu G, Yun Jong K, Desai Dhimant H
Department of Pharmacology Penn State College of Medicine, Hershey, PA 17033, USA.
Department of Medicine, Penn State College of Medicine, Hershey, PA 17033, USA.
Pharmaceuticals (Basel). 2023 Jul 26;16(8):1060. doi: 10.3390/ph16081060.
The Rho associated coiled-coil containing protein kinase (ROCK1 and ROCK2) and myotonic dystrophy-related Cdc-42 binding kinases (MRCKα and MRCKβ) are critical regulators of cell proliferation and cell plasticity, a process intimately involved in cancer cell migration and invasion. Previously, we reported the discovery of a novel small molecule (DJ4) selective multi-kinase inhibitor of ROCK1/2 and MRCKα/β. Herein, we further characterized the anti-proliferative and apoptotic effects of DJ4 in non-small cell lung cancer and triple-negative breast cancer cells. To further optimize the ROCK/MRCK inhibitory potency of DJ4, we generated a library of 27 analogs. Among the various structural modifications, we identified four additional active analogs with enhanced ROCK/MRCK inhibitory potency. The anti-proliferative and cell cycle inhibitory effects of the active analogs were examined in non-small cell lung cancer, breast cancer, and melanoma cell lines. The anti-proliferative effectiveness of DJ4 and the active analogs was further demonstrated against a wide array of cancer cell types using the NCI-60 human cancer cell line panel. Lastly, these new analogs were tested for anti-migratory effects in highly invasive MDA-MB-231 breast cancer cells. Together, our results demonstrate that selective inhibitors of ROCK1/2 (DJE4, DJ-Allyl) inhibited cell proliferation and induced cell cycle arrest at G2/M but were less effective in cell death induction compared with dual ROCK1/2 and MRCKα/β (DJ4 and DJ110).
含Rho相关卷曲螺旋蛋白激酶（ROCK1和ROCK2）以及强直性肌营养不良相关的Cdc-42结合激酶（MRCKα和MRCKβ）是细胞增殖和细胞可塑性的关键调节因子，这一过程与癌细胞的迁移和侵袭密切相关。此前，我们报道了一种新型小分子（DJ4），它是ROCK1/2和MRCKα/β的选择性多激酶抑制剂。在此，我们进一步研究了DJ4在非小细胞肺癌和三阴性乳腺癌细胞中的抗增殖和凋亡作用。为了进一步优化DJ4对ROCK/MRCK的抑制效力，我们构建了一个包含27种类似物的文库。在各种结构修饰中，我们鉴定出另外四种具有增强ROCK/MRCK抑制效力的活性类似物。在非小细胞肺癌、乳腺癌和黑色素瘤细胞系中检测了这些活性类似物的抗增殖和细胞周期抑制作用。使用NCI-60人类癌细胞系面板，进一步证明了DJ4和活性类似物对多种癌细胞类型具有抗增殖效果。最后，在高侵袭性的MDA-MB-231乳腺癌细胞中测试了这些新类似物的抗迁移作用。总之，我们的结果表明，ROCK1/2的选择性抑制剂（DJE4、DJ-烯丙基）抑制细胞增殖并诱导细胞周期在G2/M期停滞，但与ROCK1/2和MRCKα/β的双重抑制剂（DJ4和DJ110）相比，在诱导细胞死亡方面效果较差。
