Kang Chung Hyo, Kim Eun-Young, Kim Hyoung Rae, Lee Chong Ock, Lee Heung Kyoung, Jeong Hye Gwang, Choi Sang Un, Yun Chang-Soo, Hwang Jong Yeon, Lee Joo-Youn, Son You Hwa, Ahn Sunjoo, Lee Byung Hoi, Jung Heejung, Park Chi Hoon
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea.
Cancer Lett. 2016 May 1;374(2):272-8. doi: 10.1016/j.canlet.2016.02.009. Epub 2016 Feb 26.
Ceritinib, an ALK inhibitor, was hurriedly approved by the US FDA last year, and demonstrates impressive results in EML4-ALK positive patients. To get a superior ALK inhibitor, we synthesized several ceritinib derivatives with minor modifications to the phenylpiperidine moiety. Biochemical and cellular assays demonstrated the improved activity of KRCA-386 over that of ceritinib. KRCA-386 has superior inhibitory activity against ALK mutants commonly found in crizotinib-resistant patients. Particularly, KRCA-386 has considerably greater activity than ceritinib against the G1202R mutant, one of the most challenging mutations to overcome. The cell cycle analysis indicates that ALK inhibitors induce G1/S arrest, resulting in apoptosis. The in vivo xenograft data also demonstrate that KRCA-386 is significantly better than ceritinib. KRCA-386 dosed at 25 mpk caused 105% tumor growth inhibition (TGI) compared to 72% TGI with ceritinib dosed at 25 mpk. (n = 8, P = 0.010) The kinase profiling assay revealed that several kinases, which are known to be critical for tumor growth, are inhibited by KRCA-386, but not by ceritinib. We anticipate that this characteristic of KRCA-386 enhances its in vivo efficacy. In addition, KRCA-386 shows excellent blood brain barrier penetration compared to ceritinib. These results suggest that KRCA-386 could be useful for crizotinib-resistant patients with brain metastases.
色瑞替尼是一种ALK抑制剂，去年被美国食品药品监督管理局（US FDA）紧急批准，在EML4-ALK阳性患者中显示出令人印象深刻的效果。为了获得一种更优的ALK抑制剂，我们合成了几种对苯基哌啶部分进行了微小修饰的色瑞替尼衍生物。生化和细胞实验表明，KRCA-386的活性优于色瑞替尼。KRCA-386对克唑替尼耐药患者中常见的ALK突变体具有更强的抑制活性。特别是，KRCA-386对G1202R突变体的活性比色瑞替尼高得多，G1202R突变体是最难克服的突变之一。细胞周期分析表明，ALK抑制剂诱导G1/S期阻滞，从而导致细胞凋亡。体内异种移植数据也表明，KRCA-386明显优于色瑞替尼。与25mg/kg剂量的色瑞替尼导致72%的肿瘤生长抑制（TGI）相比，25mg/kg剂量的KRCA-386导致105%的肿瘤生长抑制（n = 8，P = 0.010）。激酶谱分析显示，KRCA-386可抑制几种已知对肿瘤生长至关重要的激酶，而色瑞替尼则不能。我们预计KRCA-386的这一特性会增强其体内疗效。此外，与色瑞替尼相比，KRCA-386显示出优异的血脑屏障穿透能力。这些结果表明，KRCA-386可能对伴有脑转移的克唑替尼耐药患者有用。
