title: Structure and ligand-based design of mTOR and PI3-kinase inhibitors leading to the clinical candidates VS-5584 (SB2343) and SB2602.
abstract: Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) act as critical effectors in a commonly deregulated cell signaling pathway in human cancers. The abnormal activation of the PI3K/mTOR pathway has been shown to play a role in initiation, progression, and metastasis of human tumors. Being one of the most frequently activated pathways in cancer, much effort has been directed toward inhibition of the PI3K/mTOR pathway as a novel oncology therapy. Previous work by a number of groups has revealed several selective PI3K and dual mTOR/PI3K inhibitors. However, there are few reports of therapeutic agents with a pan-PI3K/mTOR inhibitory profile within a narrow concentration range. We therefore initiated a drug discovery project with the aim of discovering dual mTOR/PI3K inhibitors which would equipotently inhibit the 4 isoforms of PI3K, α, β, γ, and δ, and mTOR a compelling profile for powerful blockage of the PI3K/mTOR pathway. A pharmacophore model was generated and used for designing a series of novel compounds, based on a purine scaffold, which potently inhibited mTOR and PI3Ks. These compounds contained a phenol headgroup essential for binding to the target proteins. Early efforts concentrated on finding replacements for the phenol as it was rapidly conjugated resulting in a short half-life in vivo. Compounds with a variety of headgroups were docked into the PI3Kα and mTOR ATP-binding sites, and aminopyrimidine and aminopyrazine were found to make excellent phenol replacements. Further structure guided optimization of side chains in the 8- and 9-positions of the purine resulted in potent inhibitors with good PKDM properties. As the PI3 kinases play a role in insulin signaling, it is believed that targeting mTOR selectively may give the benefit of blocking the AKT-pathway while avoiding the potential side effects associated with PI3K inhibition. As a result we designed a further series of selective mTOR kinase inhibitors. The project was successfully concluded by progressing both a dual mTOR/PI3K inhibitor, SB2343, and a selective mTOR inhibitor, SB2602, into preclinical development. SB2343 has since entered phase 1 clinical development as VS-5584.
authors.affiliation: S*BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore, Singapore 117 528.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Harish
authors.initials: H
authors.lastname: Nagaraj
authors.forename: Angeline
authors.initials: A
authors.lastname: Lee
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Blanchard
authors.forename: Chang Kai
authors.initials: CK
authors.lastname: Soh
authors.forename: Dizhong
authors.initials: D
authors.lastname: Chen
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Stefan
authors.initials: S
authors.lastname: Hart
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D053961:Azabicyclo Compounds / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011487:Protein Conformation; D011687:Purines / Q000378:metabolism / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D053961:Azabicyclo Compounds; D004791:Enzyme Inhibitors; D008024:Ligands; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D058570:TOR Serine-Threonine Kinases; C000599652:SB2602; C585120:VS-5584