Sun Jufeng, Baker Jennifer R, Russell Cecilia C, Pham Hong N T, Goldsmith Chloe D, Cossar Peter J, Sakoff Jennette A, Scarlett Christopher J, McCluskey Adam
Chemistry, School of Environmental & Life Sciences, The University of Newcastle University Drive Callaghan NSW 2308 Australia
Medicinal Chemistry, School of Pharmacy, Binzhou Medical University Yantai 264003 China.
RSC Med Chem. 2023 Jul 5;14(11):2246-2267. doi: 10.1039/d2md00289b. eCollection 2023 Nov 15.
From lead 1, (-(4-((4-(3-(4-(3-methoxyphenyl)-1-1,2,3-triazol-1-yl)propyl)piperazin-1-yl)sulfonyl)-phenyl)acetamide), a S100A2-p53 protein-protein interaction inhibitor based on an modelling driven hypothesis, four focused libraries were designed and synthesised. Growth inhibition screening was performed against 16 human cancer cell lines including the pancreatic cell lines MiaPaCa2, BxPC3, AsPC-1, Capan-2, HPAC, PANC-1 and the drug resistant CFPAC1. Modification of 1's phenylacetamide moiety, gave with only modest pancreatic cancer activity. Modification of the 3-OCHPh moiety () gave 4-CH (26), 4-CHCH (27), 4-CF (31) and 4-NO (32) with sterically bulky groups more active. A 4-CF acetamide replacement enhanced cytotoxicity (). The 4-C(CH)36 resulted in a predicted steric clash in the S100A2-p53 binding groove, with a potency decrease. Alkyl moieties afforded more potent analogues, 34 (4-CH) and 35 (CHCH), a trend evident against pancreatic cancer: GI 3.7 (35; BxPC-3) to 18 (40; AsPC-1) μM. analogues with a 2-CF and 3-CF benzenesulfonamide moiety were less active than the corresponding analogues. Two additional analogues were designed: 51 (4-CF; 4-OCH) and 52 (4-CF; 2-OCH) revealed 52 to be 10-20 fold more active than 51, against the pancreatic cancer cell lines examined with sub-micromolar GI values 0.43 (HPAC) to 0.61 μM (PANC-1). MOE calculated binding scores for each pose are also consistent with the observed biological activity with 52. The obtained SAR data is consistent with the proposed interaction within the S100A2-p53 bonding groove.
基于建模驱动假设的S100A2-p53蛋白-蛋白相互作用抑制剂1（-(4-((4-(3-(4-(3-甲氧基苯基)-1H-1,2,3-三唑-1-基)丙基)哌嗪-1-基)磺酰基)-苯基)乙酰胺），设计并合成了四个聚焦文库。针对16种人类癌细胞系进行了生长抑制筛选，包括胰腺癌细胞系MiaPaCa2、BxPC3、AsPC-1、Capan-2、HPAC、PANC-1以及耐药的CFPAC1。对1的苯乙酰胺部分进行修饰，得到的化合物仅具有适度的胰腺癌活性。对3-OCHPh部分（）进行修饰，得到带有空间位阻较大基团的4-CH（26）、4-CHCH（27）、4-CF（31）和4-NO（32），活性更高。4-CF乙酰胺替代物增强了细胞毒性（）。4-C(CH)36在S100A2-p53结合凹槽中导致预测的空间冲突，活性降低。烷基部分提供了更有效的类似物，34（4-CH）和35（CHCH）, 这一趋势在针对胰腺癌的实验中很明显：GI为3.7（35；BxPC-3）至18（40；AsPC-1）μM。具有2-CF和3-CF苯磺酰胺部分的类似物比相应的类似物活性更低。另外设计了两种类似物：51（4-CF；4-OCH）和52（4-CF；2-OCH），结果显示52比51的活性高10至20倍，在所检测的胰腺癌细胞系中，其亚微摩尔GI值为0.43（HPAC）至0.61μM（PANC-1）。MOE计算的每个构象的结合分数也与52所观察到的生物活性一致。所获得的SAR数据与S100A2-p53结合凹槽内提出的相互作用一致。
