Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities

Abstract

By repurposing a typical dopamine D1/D5 receptor agonist motif, C1-substituted-N3-benzazepine or benzazecine, into the classical RTK inhibitor 2,4-diaminopyrimidine skeleton, a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) were developed. Compounds 7 and 8a were identified possessing high potency against both c-Met and ALK kinases. Compound 8a displayed appreciable antitumor efficacy at the dose of 1 mg/kg in the ALK-driven BF3/EML4-ALK xenograft mice model.

Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold

“…We then evaluated the inhibitory effects of these compounds on the cell proliferation by using the protocol we previously reported. 47,48 As shown in Table 4, in the c-Met addicted NSCLC EBC-1 cells, seven compounds (12, 28a-d, 28f and 28h) outperformed the other counterparts with significant antiproliferative effects (IC 50 s less than 1 µM). However, these compounds suffered from a significant decrease in enzyme-tocell shift, likely due to their poor cellular penetration.…”

“…47,48 Compound 1 and panatinib were used as the reference compounds 28,31 for c-Met and VEGFR2 respectively. As shown in Fig.…”

“…To further examine its kinase selectivity, compound 28a was evaluated for the inhibitory effects against a panel of our in-house 14 RTKs. 47,48 As shown in Table 5, in addition to c-Met, compound 28a only inhibited tyrosine kinase VEGFR2 at the concentration of 0.1 µM, suggesting that 28a was a relatively selective c-Met inhibitor, which was superior to cabozantinib 1.…”

Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing bicyclic aminobenzazepines for anaplastic lymphoma kinase (ALK) inhibitor

“…In our effort to discover potent ALK inhibitors, [16][17][18] we came up with hybridized structures of LDK378 and CEP-37440, thereby leading to a novel structure, KRCAs, which is 2,4-diaminopyrimidine bearing 4-(isopropylsulfonyl)anilino and bicyclic benzazepine moiety as shown in Figure 2. Although Liu et al recently reported 2,4-diarylaminopyrimidine analog bearing bicyclic benzazepine moiety and methylacetamidoaniline as a c-Met/ALK multikinase inhibitor, [19] its chemical features differ from KRCAs. Herein, we report the synthesis of KRCAs and their anti-ALK activities in biochemical and cellular assays as well as PK and in vivo xenograft data of the selected compounds.…”

“…Moreover, it was reported that ceritinib inhibited both ALK and IGF-1R, thereby showing better potency in in vivo study, compared to crizotinib. [19] Likewise, KRCA-0445 targeting both ALK and IGF-1R might give clinical benefits in the future development.…”