title: 6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors.
abstract: Isoform-selective inhibition of PI3K-α has been identified as one of the important strategy to discover effective and safer anticancer agents. Herein, we report discovery of 'quinazoline' as a new chemotype for isoform-selective PI3K-α inhibitors. The indolyl substituted quinazoline 9u displayed selective inhibition of PI3K-α with IC50 value of 0.201 μM with >49.7 over PI3K-β, and δ-isoforms. Quinazoline 9u also inhibited PI3K-γ with IC50 value of 0.750 μM (3.7 fold selective for α-versus γ-isoform). The isoform-selective inhibition was also demonstrated at protein-expression level by western-blot analysis in MCF-7 and PC-3 cells. The isoform-selective inhibitor 9u also showed inhibition of phospho-Akt levels in these cells. Quinazoline 9u showed in-vitro cytotoxicity in MCF-7 cells with GI50 of 7 μM, which was highly selective for cancer cells, as it was non-toxic to normal cells fR2, HEK293 and hGF (GI50 > 50 μM). Compound 9u at 25 mg/kg dose showed 62 and 37% TGI in Ehrlich Ascites Carcinoma and Ehrlich Solid Tumor mice models. In nutshell, our efforts to identify potent and efficacious PI3K inhibitors resulted in the discovery of a new class of isoform-selective PI3K-α inhibitors possessing promising in-vivo anticancer activity.
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Rammohan R
authors.initials: RR
authors.lastname: Yadav
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Guru
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Mahajan
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Mubashir J
authors.initials: MJ
authors.lastname: Mintoo
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Preformulation Laboratory, PKPD Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Preformulation Laboratory, PKPD Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Sonali S
authors.initials: SS
authors.lastname: Bharate
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Dilip M
authors.initials: DM
authors.lastname: Mondhe
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India. Electronic address: sbhushan@iiim.ac.in.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India. Electronic address: sbharate@iiim.ac.in.
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D010539:Permeability; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: 6-aryl quinazolines; Anticancer agents; Breast cancer; Isoform-selective; PI3K-alpha