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Discovery of N-(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors.

ABSTRACT: The JAK2^V617F mutation leads to JAK2 autophosphorylation and activation of downstream pathways, eventually resulting in myeloproliferative neoplasms (MPNs). Selective inhibitors showed advantages in terms of side effects; therefore, there is an urgent need to develop novel selective JAK2 inhibitors for treating MPNs. In this study, we described a series of N-(4-(aminomethyl)phenyl)pyrimidin-2-amine derivatives as selective JAK2 inhibitors. Systematic exploration through opening the tetrahydroisoquinoline based on the previous lead compound 13ac led to the discovery of the optimal compound A8. Compound A8 showed excellent potency on JAK2 kinase, with an IC₅₀ value of 5 nM, and inhibited the phosphorylation of JAK2 and its downstream signaling pathway. Moreover, A8 exhibited 38.6-, 54.6-, and 41.2-fold selectivity for JAK1, JAK3, and TYK2, respectively. Compared to the lead compound, A8 demonstrated much better metabolic stabilities, with a bioavailability of 41.1%. These findings suggest that A8 is a relatively selective JAK2 inhibitor, deserving to be developed for treating MPNs.

SUBMITTER: Tian Y

PROVIDER: S-EPMC10424325 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Discovery of N-(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors.

Tian Yang Y Qin Songhui S Zhang Fang F Luo Jing J He Xi X Sun Yi Y Yang Tao T

ACS medicinal chemistry letters 20230801 8

The JAK2V617F mutation leads to JAK2 autophosphorylation and activation of downstream pathways, eventually resulting in myeloproliferative neoplasms (MPNs). Selective inhibitors showed advantages in terms of side effects; therefore, there is an urgent need to develop novel selective JAK2 inhibitors for treating MPNs. In this study, we described a series of N-(4-(aminomethyl)phenyl)pyrimidin-2-amine derivatives as selective JAK2 inhibitors. Systematic exploration through opening ...[more]

PMID: 37583815

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Project description:Increased expression of the serine protease urokinase-type plasminogen activator (uPA) in tumor tissues is highly correlated with tumor cell migration, invasion, proliferation, progression, and metastasis. Thus inhibition of uPA activity represents a promising target for antimetastatic therapy. So far, only the x-ray crystal structure of uPA inactivated by H-Glu-Gly-Arg-chloromethylketone has been reported, thus limited data are available for a rational structure-based design of uPA inhibitors. Taking into account the trypsin-like arginine specificity of uPA, (4-aminomethyl)phenylguanidine was selected as a potential P1 residue and iterative derivatization of its amino group with various hydrophobic residues, and structure-activity relationship-based optimization of the spacer in terms of hydrogen bond acceptor/donor properties led to N-(1-adamantyl)-N'-(4-guanidinobenzyl)urea as a highly selective nonpeptidic uPA inhibitor. The x-ray crystal structure of the uPA B-chain complexed with this inhibitor revealed a surprising binding mode consisting of the expected insertion of the phenylguanidine moiety into the S1 pocket, but with the adamantyl residue protruding toward the hydrophobic S1' enzyme subsite, thus exposing the ureido group to hydrogen-bonding interactions. Although in this enzyme-bound state the inhibitor is crossing the active site, interactions with the catalytic residues Ser-195 and His-57 are not observed, but their side chains are spatially displaced for steric reasons. Compared with other trypsin-like serine proteases, the S2 and S3/S4 pockets of uPA are reduced in size because of the 99-insertion loop. Therefore, the peculiar binding mode of the new type of uPA inhibitors offers the possibility of exploiting optimized interactions at the S1'/S2' subsites to further enhance selectivity and potency. Because crystals of the uPA/benzamidine complex allow inhibitor exchange by soaking procedures, the structure-based design of new generations of uPA inhibitors can rely on the assistance of x-ray analysis.

Project description:IntroductionPhosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting PI3Kα have attracted considerable interest in recent years. Molecular hybridization, with the advantage of simplified pharmacokinetics and drug-drug interactions, emerged as one of the important avenues for discovering potential drugs.ObjectivesThis study aimed to construct PI3Kα inhibitors by hybridization and investigate their antitumor activity and mechanism.Methods26 quinazoline-2-indolinone derivatives were obtained by molecular hybridization, and their structure-activity relationship was analyzed by MTT, in vitro kinase activity and molecular docking. The biological evaluation of compound 8 was performed by transwell, flow cytometry, laser scanning confocal microscopy, Western blot, CTESA and immunohistochemistry.ResultsHere, we employed molecular hybridization methods to construct a series of quinazoline-2-indolinone derivatives as PI3Kα selective inhibitors. Encouragingly, representative compound 8 exhibited a PI3Kα enzymatic IC50 value of 9.11 nM and 10.41/16.99/37.53-fold relative to the biochemical selectivity for PI3Kβ/γ/δ, respectively. Moreover, compound 8 effectively suppressed the viability of B16, HCT116, MCF-7, H22, PC-3, and A549 cells (IC50 values: 0.2 μM ∼ 0.98 μM), and dramatically inhibited the proliferation and migration of NSCLC cells, as well as induced mitochondrial apoptosis through the PI3K/Akt/mTOR pathway. Importantly, compound 8 demonstrated potent in vivo anti-tumor activity in non-small cell lung cancer mouse models without visible toxicity.ConclusionsThis study presented a new avenue for the development of PI3Kα inhibitors and provided a solid foundation for novel QHIDs as potential future therapies for the treatment of NSCLC.

Dataset Information

Discovery of N-(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors.

Publications

Discovery of <i>N</i>-(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors.

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