Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor

Abstract

JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective JAK1 kinase inhibitor, is reported. Compound 21 has good preclinical pharmacokinetics. Compound 21 displayed an enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model.

Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors

“…The chlorobenzyl end of the compound was enclosed within the hydrophobic pocket under the P-loop and formed interactions with hydrophobic residues such as F886 and V889. This conformation of compound 42 was similar to the conformation of the selective JAK1 inhibitor (LKT) reported from the X-ray crystallography experiment by Su et al 31 . The carboxamide moiety from pyrrolopyridine extended towards the bulk solved.…”

“…The chlorobenzyl moiety folded inward into the hydrophobic pocket formed by the residues from the activation loop, αC-helix, and the P-loop. This folding of the chlorobenzyl moiety towards the hydrophobic pocket was reminiscent of the conformation observed in the crystallographic structure of the selective JAK1 inhibitor LKT (PDB ID 6SM8 ) reported by Su et al 31 . The binding conformation of compound 42 selected from the docking analysis was prepared for further molecular dynamics simulation study.…”

Dual targeting of cytokine storm and viral replication in COVID-19 by plant-derived steroidal pregnanes in silico

“…In comparison with the reference inhibitor, ruxolitnib, the top-three ranked PDPs (atratogenin B, hirundigenin, glaucogenin C) with the best binding modes, for whichhJAK1 had the highest a nities, interacted with the hinge residues LEU 959 , GLU 957 and the side chain of ASN 1008 and the backbone carbonyl oxygen of ARG 1007 of the catalytic residues. These residues are involved in the inhibitory activities of selected compounds in both in silico and in vitro analyses [60][61][62].…”

Anticancer Mechanism of Withania Somnifera and Its Bioactive Compounds : A Short Review Along with Computational Molecular Docking Study

“…Two dimensional structure of Withanolide [59] and Withaferin-A [60] were retrieved from PubChem database and saved as "sdf" format for docking analysis (showed in Figure 1) The crystal structure of macromolecules named 1SVC (NUCLEAR FACTOR KAPPA-B (NF-KB)) [61], 6SMB (Tyrosine-protein kinase JAK1) [62], 2YUU (Protein kinase C delta type) [63], 6MXY (TP53binding protein 1) [64], 1ILQ (Interleukin-8 receptor A) [65], 3S7S (Cytochrome P450 19A1) [66], 1A9U (MAP KINASE P38) [67], 6XIH (Mitogen-activated protein kinase) [68], 3A8X (Protein kinase C iota type) [69] were collected from protein data bank online database. Unwanted ions, ligands and water molecules were removed from protein structure using PYMOL software [70].…”