title: Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1).
abstract: Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.
authors: Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States. sean.murphy@takedasd.com
authors: Sean T
authors: ST
authors: Murphy
authors: Gordon
authors: G
authors: Alton
authors: Simon
authors: S
authors: Bailey
authors: Sangita M
authors: SM
authors: Baxi
authors: Benjamin J
authors: BJ
authors: Burke
authors: Thomas A
authors: TA
authors: Chappie
authors: Jacques
authors: J
authors: Ermolieff
authors: RoseAnn
authors: R
authors: Ferre
authors: Samantha
authors: S
authors: Greasley
authors: Michael
authors: M
authors: Hickey
authors: John
authors: J
authors: Humphrey
authors: Natasha
authors: N
authors: Kablaoui
authors: John
authors: J
authors: Kath
authors: Steven
authors: S
authors: Kazmirski
authors: Michelle
authors: M
authors: Kraus
authors: Stan
authors: S
authors: Kupchinsky
authors: John
authors: J
authors: Li
authors: Laura
authors: L
authors: Lingardo
authors: Matthew A
authors: MA
authors: Marx
authors: Dan
authors: D
authors: Richter
authors: Steven P
authors: SP
authors: Tanis
authors: Khanh
authors: K
authors: Tran
authors: William
authors: W
authors: Vernier
authors: Zhi
authors: Z
authors: Xie
authors: Min-Jean
authors: MJ
authors: Yin
authors: Xiao-Hong
authors: XH
authors: Yu
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005021:Ethylamines; D011725:Pyridines; D011758:Pyrroles; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt