Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

Abstract

Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2,4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized. One of the best compounds, 31 (CZh226), showed remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase selectivity profile. Moreover, this compound potently inhibited the migration and invasion of A549 tumor cells by regulating the PAK4-directed downstream signaling pathways in vitro. Taken together, these data support the further development of 31 as a lead compound for PAK4-targeted anticancer drug discovery and as a valuable research probe for the further biological investigation of group II PAKs.

P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer

“…Xu et al developed 2-arylamino-4-aryl-pyrimidines as potent PAK1 inhibitors, with compound 12 showing potent inhibitory activity against PAK1, but the cell activity was not evaluated 189 . In order to improve the selectivity against PAK1, the 5-cyclopropyl-1H-pyrazole group was incorporated into the 4-site of aminopyrimidine core for targeting the ribose pocket to yield a series of potent, selective PAK1 inhibitors, including compounds 13 , 14, and 15 190 - 192 . To mitigate the toxicity, a pyridone side chain analog G-9791 was discovered as a selective PAK1 inhibitor 193 .…”

Synthesis of (R) and (S)-3-Chloro-5-(2,4-dimethylpiperazin-1-yl)-4H-1,2,6-thiadiazin-4-ones

“…While the main purpose of the added methyl group is to The incorporation of an asymmetric 3-methyl substituent to the piperazine moiety can improve the biological activity of a compound and enhance its physicochemical characteristics. There are many examples in the literature of 3-methylpiperazines exhibiting anti-cancer activity [5], or acting as antiplatelet agents [6], among others.…”

“…There are numerous examples of compounds where the 3-methylpiperazine substituent has had a pronounced effect on the overall profile of the compound (Figure 2) [5,8,9]. In the case of Talmapimod (SCIO-469), the incorporation of a 3-methylpiperazine into the structure helped reduce the metabolism of an adjacent benzyl group [8].…”

Funcionalização de compostos N-heterocí­clicos visando a sí­ntese de substâncias bioativas

“…Embora esse tipo de reação continue sendo aplicado até os dias de hoje, algumas desvantagens como condições reacionais drásticas (necessidade de uso de bases fortes e de altas temperaturas) e restrito escopo de substratos podem limitar o uso dessa estratégia. 2) no solvente que pode ser isopropanol, THF, DMF ou CH3CN; 3) e na temperatura que varia desde 0 °C até temperaturas de refluxo, as quais podem ser por aquecimento convencional ou por irradiação de micro-ondas (FAN et al, 2018;HAO et al, 2018;KRAPF et al, 2019;KRAPF;GALLUS;WIESE, 2017;MPHAHLELE et al, 2018;SHEN et al, 2016;VAN HORN et al, 2014).…”

“…Esquema 21. Resumo de algumas metodologias de preparação de 4-aminoquinazolinas por SNAr Fonte: FAN et al, 2018;HAO et al, 2018;KRAPF et al, 2019;KRAPF;GALLUS;WIESE, 2017;MPHAHLELE et al, 2018;SHEN et al, 2016;VAN HORN et al, 2014 Vale • Preparar algumas quinazolinonas N-protegidas e quinazolinas halogenadas para o estudo de funcionalização;…”