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A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4) inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC50 < 1 μM). Among them, compounds 8d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC50 = 0.060 μM and 0.068 μM, respectively). Furthermore, we observed that compounds 8d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line. In addition, molecular docking analysis was performed to predict the possible binding mode of compound 8d. This series of compounds has the potential for further development as PAK4 inhibitors for anticancer activity. [ABSTRACT FROM AUTHOR]

Herein, we report the discovery process and antitumor activity of the TRK inhibitor CZw-124 (8o), which is a quinazoline derivative. Starting from a PAK4 inhibitor, we used various drug design strategies, including pharmacophore feature supplementation, F-scanning, and blocking metabolic sites, and finally found a TRK inhibitor CZw-124 that is effective in vitro and in vivo. Docking studies and molecular dynamics simulations revealed a possible mode of binding of CZw-124 to TRKA. Biological activity evaluation showed that CZw-124 belongs to a class of pan-TRK inhibitors with moderate kinase selectivity. It inhibited the proliferation and induced the apoptosis of Km-12 cells in vitro by interfering with the phosphorylation of TRKA. Pharmacodynamic evaluation in vivo showed that CZw-124 had a tumor inhibition rate comparable to that of larotrectinib after oral administration of 40 mg/kg/d (tumor growth inhibiton = 71%). [Display omitted] • Using rational drug design strategies strategies, a potent pan-TRK inhibitor 8o was found. • Compound 8o effectively inhibited the proliferation and induced the apoptosis of Km-12 cells. • Good metabolic properties in vitro and moderate pharmacokinetic properties in vivo of compound 8o were observed. • Compound 8o possesses good pharmacodynamic performance in vivo. [ABSTRACT FROM AUTHOR]

Tropomyosin receptor kinase (TRK) is an ideal target for treating cancers caused by the NTRK gene fusion. In this study, more than 60 2,4-diaminopyrimidine derivatives were prepared to understand the structure-activity relationship and confirm the rationality of the pharmacophore model reported previously. Among them, compound 19k was found to be a potent pan-TRK inhibitor that inhibits the proliferation of Km-12 cell lines. Additionally, compound 19k induced the apoptosis of Km-12 cells in a concentration-dependent manner. Western blot analysis revealed that compound 19k inhibited the phosphorylation of TRK to block downstream pathways. Compound 19k also possessed outstanding plasma stability and liver microsomal stability in vitro , with half-lives greater than 289.1 min and 145 min, respectively. Pharmacokinetic studies indicated that the oral bioavailability of compound 19k is 17.4%. These results demonstrate that compound 19k could serve as a novel lead compound for overcoming NTRK- fusion cancers. [Display omitted] • Using rational drug design strategies, a potent pan-TRK inhibitor 19k was found. • Compound 19k inhibited the proliferation and induced the apoptosis of Km-12 and the mechanism had also been explored. • Good metabolic properties in vitro and moderate pharmacokinetic properties in vivo of compound 19k were observed. • Reasonable theoretical hypotheses and a large number of experimental verifications jointly explained the SAR. [ABSTRACT FROM AUTHOR]

The tropomyosin receptor kinases TRKs are responsible for different tumor types which caused by NTRK gene fusion, and have been identified as a successful target for anticancer therapeutics. Herein, we report a potent and selectivity TRKs inhibitor 19m through rational drug design strategy from a micromolar potency hit 17a. Compound 19m significantly inhibits the proliferation of TRK-dependent cell lines (Km-12), while it has no inhibitory effect on TRK-independent cell lines (A549 and THLE-2). Furthermore, kinases selectivity profiling showed that in addition to TRKs, compound 19m only displayed relatively strong inhibitory activity on ALK. These data may indicate that compound 19m has a good drug safety. Partial ADME properties were evaluated in vitro and in vivo. Compound 19m exhibited a good AUC values and volume of distribution and low clearance in the pharmacokinetics experiment of rats. Finally, a pharmacophore model guided by experimental results is proposed. We hope this theoretical model can help researchers find type I TRK inhibitors more efficiently. [Display omitted] • Using rational drug design strategies, a TRK inhibitor 19m with potent activity and good selectivity was obtained. • Compound 19m possesses good ADME properties in vitro and in vivo , such as favorable plasma stability, and good pharmacokinetics properties, etc. • A more accurate pharmacophore model based on structure-activity relationship analysis has been constructed. [ABSTRACT FROM AUTHOR]

NTRK gene fusion leads to the activation of downstream signaling pathways, which is a oncogenic driver in various cancers. NTRK fusion-positive cancers can be treated with the first-generation TRK inhibitors, larotrectinib and entrectinib. Unfortunately, the patients eventually face the dilemma of no drugs available as the emergence of certain resistance mutations. The development of efficient and broad-spectrum second-generation TRK inhibitors is still of great significance. Here, we analyzed the binding modes of compounds 6 , 10 with TRKA protein, respectively, a series of novel indazole TRK inhibitors were designed and synthesized using molecular hybridization strategy. Among them, the optimal compound B31 showed strong antiproliferative activities against Km-12, Ba/F3-TRKAG595R, and Ba/F3-TRKAG667C cell lines with IC 50 values of 0.3, 4.7, and 9.9 nM, respectively. And the inhibitory effect against TRKAG667C (IC 50 = 9.9 nM) was better than that of selitrectinib (IC 50 = 113.1 nM). Further, compound B31 exhibited moderate kinase selectivity and excellent plasma stability (t 1/2 > 480 min). In vivo pharmacokinetic studies in Sprague-Dawley rats showed that B31 had acceptable pharmacokinetic properties. [Display omitted] • Based on molecular hybridization strategy, novel TRK inhibitors were discovered. • B31 exhibited significant inhibitory potency against multiple TRK mutants. • B31 possessed a moderate kinase selectivity. • B31 displayed good antiproliferative activities against NTRK fusion positive cells. • B31 showed excellent plasma stability and moderate pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Tropomyosin receptor kinase (TRK) is a promising target for treating NTRK fusion cancers. The solvent front and xDFG mutations induced by larotrectinib and entrectinib result in acquired resistance in advanced-stage patients. In this study, we report a highly potent and selective type II TRK inhibitor, 40l , developed using a structure-based design strategy. Compound 40l significantly suppressed Km-12, Ba/F3-TRKAG595R, and Ba/F3-TRKAG667C cell proliferation. In biochemical and cellular assays, 40l showed better inhibitory activity against TRKAG667C than that by the positive control, selitrectinib. Additionally, it induced apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells in a dose-dependent manner. Furthermore, 40l showed good selectivity for a panel of 41 kinases. In vitro assays indicated that 40l possessed outstanding plasma stability and moderate liver microsomal stability. Based on the above results, compound 40l could be further optimized to overcome the solvent front and xDFG TRK mutations. [Display omitted] • Based on structure-based design strategy, novel type II TRK inhibitors were discovered. • 40l exhibits significant inhibitory potency against multiple TRK mutants. • 40l induces the apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells. • 40l showed excellent plasma stability and moderate liver microsomal stability. • 40l possess a good selectivity in a panel of 41 kinase. [ABSTRACT FROM AUTHOR]

Tropomyosin receptor kinases (TRKs) are effective targets for anti-cancer drug discovery. The first-generation type I TRKs inhibitors, larotrectinib and entrectinib, exhibit durable disease control in the clinic. The emergence of acquired resistance mediated by secondary mutations in the TRKs domain significantly reduces the therapeutic efficacy of these two drugs, indicating an unmet clinical need. In this study, we designed a potent and orally bioavailable TRK inhibitor, compound 24b , using a molecular hybridization strategy. Compound 24b exhibited significant inhibitory potency against multiple TRK mutants in both biochemical and cellular assays. Furthermore, compound 24b induced apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells in a dose-dependent manner. Additionally, compound 24b exhibited moderate kinase selectivity. In vitro stability revealed that compound 24b showed excellent plasma stability (t 1/2 > 289.1 min) and moderate liver microsomal stability (t 1/2 = 44.3 min). Pharmacokinetic studies have revealed that compound 24b is an orally bioavailable TRK inhibitor with a good oral bioavailability of 116.07%. These results indicate that compound 24b be used as a lead molecule for further modifications to overcome drug-resistant mutants of TRK. [Display omitted] • Based on molecular hybridization strategy, novel TRK inhibitors were discovered. • 24b exhibits significant inhibitory potency against multiple TRK mutants. • 24b induces the apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells. • 24b showed excellent plasma stability and moderate liver microsomal stability. • 24b possess a good oral bioavailability. [ABSTRACT FROM AUTHOR]

• A library of 2,4-disubstituted-7 H -pyrrolo[2,3- d pyrimidine derivatives were designed and synthesized. • Most compounds suppressed the enzymatic activities of FAK with IC 50 values of 10−8–10−9 M. • 18h exhibited potent enzyme inhibition against FAK (IC 50 = 19.1 nM). • 18h potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cell lines. • 18h induced apoptosis and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7 H -pyrrolo[2,3- d pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC 50 = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC 50 values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC 50 = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery. [ABSTRACT FROM AUTHOR]

A series of 7 H -pyrrolo[2,3- d pyrimidine derivatives possessing a dimethylphosphine oxide moiety were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymatic activities of FAK, with IC 50 values in the 10−8–10−9 M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b exhibited potent enzyme inhibition (IC 50 = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. 25b exhibited antiproliferative activity against A549 cells (IC 50 = 3.2 μ M) and relatively less cytotoxicity to a normal human cell line HK2. Compound 25b also induced apoptosis and suppressed the migration of A549 cells in a concentration-dependent manner. Further profiling of compound 25b revealed it had good metabolic stability in mouse, rat and human liver microsomes in vitro and showed weak inhibitory activity against various subtypes of human cytochrome P450. The docking study of compound 25b was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of FAK inhibitors. Image 1 • A series of 7 H -pyrrolo[2,3- d pyrimidine derivatives were designed and synthesized. • The compounds suppressed the enzymatic activities of FAK with IC 50 values of 10−8–10−9 M. • The compounds inhibited the proliferation of MDA-MB-231 and A549 cells. • 25b exhibited potent enzyme inhibition (IC 50 = 5.4 nM) and good selectivity. • 25b possessed good microsomal metabolic stability in vitro. [ABSTRACT FROM AUTHOR]