Kim Nam Ah, Hong Sungyoul, Kim Ki Hyun, Choi Du Hyung, Kim Joo Seok, Park Kyung Eui, Choi Jun Young, Shin Young Kee, Jeong Seong Hoon
College of Pharmacy, Dongguk University-Seoul, Gyeonggi 10326, Korea.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
Pharmaceutics. 2020 Feb 3;12(2):121. doi: 10.3390/pharmaceutics12020121.
c-Met is a receptor tyrosine kinase with no commercially available product despite being a pivotal target in cancer progression. Unlike other c-Met inhibitors that fail clinically, ABN401 is a newly synthesized c-Met inhibitor that is not potentially degraded by aldehyde oxidase (AO) in human liver cytosol. This study aimed to determine the physicochemical stability, pharmacokinetics in beagle dogs, and therapeutic effect of ABN401 in a c-Met-amplified non-small-cell lung cancer (NSCLC) patient-derived xenograft (PDX) model. ABN401 was found to be a weak basic compound, with pKa and log values of 7.49 and 2.46, respectively. It is poorly water-soluble but soluble at acidic pH. The accelerated storage stability is dependent on temperature, but the purity remains at over 97% after 6 months. The bioavailability is approximately 30% in dogs and it is highly efficient in the PDX model, achieving around 90% tumor growth inhibition in combination with erlotinib. These observations indicate that the compound is acceptable for the next phase of trials.
c-Met是一种受体酪氨酸激酶，尽管它是癌症进展中的关键靶点，但目前尚无上市产品。与其他临床失败的c-Met抑制剂不同，ABN401是一种新合成的c-Met抑制剂，在人肝细胞溶质中不会被醛氧化酶（AO）潜在降解。本研究旨在确定ABN401的理化稳定性、在比格犬中的药代动力学以及在c-Met扩增的非小细胞肺癌（NSCLC）患者来源异种移植（PDX）模型中的治疗效果。发现ABN401是一种弱碱性化合物，pKa和log 值分别为7.49和2.46。它的水溶性较差，但在酸性pH下可溶。加速储存稳定性取决于温度，但6个月后纯度仍保持在97%以上。在犬中的生物利用度约为30%，在PDX模型中效率很高，与厄洛替尼联合使用时可实现约90%的肿瘤生长抑制。这些观察结果表明该化合物可用于下一阶段的试验。
