Pancreatic cancer is one of the most aggressive cancers with poor prognosis and a low 5-year survival rate. The family of P21-activated kinases (PAKs) appears to modulate many signaling pathways that contribute to pancreatic carcinogenesis. In this work, we demonstrated that PAK1 is a critical regulator in pancreatic cancer cell growth. PAK1-targeted inhibition is therefore a new potential therapeutic strategy for pancreatic cancer. Our small molecule screening identified a relatively specific PAK1-targeted inhibitor, CP734. Pharmacological and biochemical studies indicated that CP734 targets residue V342 of PAK1 to inhibit its ATPase activity. Further in vitro and in vivo studies elucidated that CP734 suppresses pancreatic tumor growth through depleting PAK1 kinase activity and its downstream signaling pathways. Little toxicity of CP734 was observed in murine models. Combined with gemcitabine or 5-fluorouracil, CP734 also showed synergistic effects on the anti-proliferation of pancreatic cancer cells. All these favorable results indicated that CP734 is a new potential therapeutic candidate for pancreatic cancer.

中文翻译：

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新型PAK1抑制剂治疗胰腺癌的鉴定。

胰腺癌是预后不良且5年生存率较低的最具侵略性的癌症之一。P21激活激酶（PAKs）家族似乎可以调节许多有助于胰腺癌发生的信号通路。在这项工作中，我们证明了PAK1是胰腺癌细胞生长的关键调节剂。因此，PAK1靶向抑制是胰腺癌的一种新的潜在治疗策略。我们的小分子筛选确定了相对特异性的针对PAK1的抑制剂CP734。药理和生化研究表明，CP734靶向PAK1的V342残基以抑制其ATPase活性。进一步的体外和体内研究表明，CP734通过消耗PAK1激酶活性及其下游信号通路来抑制胰腺肿瘤的生长。在鼠模型中，CP734的毒性很小。与吉西他滨或5-氟尿嘧啶联合使用，CP734还显示出对胰腺癌细胞抗增殖的协同作用。所有这些有利的结果表明，CP734是胰腺癌的新的潜在治疗候选物。