title: Synthesis and evaluation of pyrrolotriazine based molecules as PI3 kinase inhibitors.
abstract: Over activation of the PI3K/Akt/mTOR pathway is found in most cancer tumor types. Controlled regulation of this pathway using PI3K inhibitors can provide therapeutic significance in cancer treatment. Herein, we report the synthesis and evaluation of pyrrolotriazine based novel small molecules as pan-PI3K inhibitors. The SAR studies based on in vitro potency along with microsomal metabolic stability screening, identified 18 as a preclinical lead found to be suitable for in vivo evaluation. The identified lead was also found to be a selective inhibitor of PI3K isoforms and mTOR when screened across a panel of 23 homologous kinases.
authors.affiliation: Sphaera Pharma Pte. Ltd, Singapore 038988, Singapore.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.affiliation: Sphaera Pharma Pte. Ltd, Singapore 038988, Singapore.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Hollinger
authors.affiliation: Sphaera Pharma Pvt. Ltd, Plot 32, Sec 5, IMT Manesar, 122051, India.
authors.forename: Bilash
authors.initials: B
authors.lastname: Kuila
authors.affiliation: Sphaera Pharma Pvt. Ltd, Plot 32, Sec 5, IMT Manesar, 122051, India.
authors.forename: Reena
authors.initials: R
authors.lastname: Arora
authors.affiliation: Sphaera Pharma Pvt. Ltd, Plot 32, Sec 5, IMT Manesar, 122051, India.
authors.forename: Somdutta
authors.initials: S
authors.lastname: Sen
authors.affiliation: Sphaera Pharma Pvt. Ltd, Plot 32, Sec 5, IMT Manesar, 122051, India. Electronic address: dinesh.m@sphaerapharma.com.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Mahajan
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014227:Triazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C546842:MTOR protein, human
keywords: Kinase screening; Oncology; PI3K inhibitor; PI3K/Akt/mTOR pathway; Pyrrolotriazine