title: Discovery of 3,5-substituted 6-azaindazoles as potent pan-Pim inhibitors.
abstract: Pim kinase inhibitors are promising cancer therapeutics. Pim-2, among the three Pim isoforms, plays a critical role in multiple myeloma yet inhibition of Pim-2 is challenging due to its high affinity for ATP. A co-crystal structure of a screening hit 1 bound to Pim-1 kinase revealed the key binding interactions of its indazole core within the ATP binding site. Screening of analogous core fragments afforded 1H-pyrazolo[3,4-c]pyridine (6-azaindazole) as a core for the development of pan-Pim inhibitors. Fragment and structure based drug design led to identification of the series with picomolar biochemical potency against all three Pim isoforms. Desirable cellular potency was also achieved.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Hu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Grace Ka Yan
authors.initials: GK
authors.lastname: Chan
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Jae H
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Do
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Jake
authors.initials: J
authors.lastname: Drummond
authors.affiliation: Juno Therapeutics, 307 Westlake Ave North, Seattle, WA 98109, United States.
authors.forename: Allen
authors.initials: A
authors.lastname: Ebens
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Justin
authors.initials: J
authors.lastname: Ly
authors.affiliation: Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Moffat
authors.affiliation: BioMarin (Shanghai), Room 605, 780 Cailun Road, Pudong District, Shanghai 201203, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chao
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Heidi
authors.initials: H
authors.lastname: Wallweber
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kolesnikov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D011720:Pyrazoles; D011725:Pyridines; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: Fragment based screen; Kinase inhibitor; Lead optimization; Pim kinases; Screening; Structure based drug design