Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors.
There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: pastor.richard@gene.com.
Richard M
RM
Pastor
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Jason D
JD
Burch
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Steven
S
Magnuson
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Daniel F
DF
Ortwine
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Yuan
Y
Chen
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Kelly
K
De La Torre
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Xiao
X
Ding
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Charles
C
Eigenbrot
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Adam
A
Johnson
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Marya
M
Liimatta
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Yichin
Y
Liu
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Steven
S
Shia
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Xiaolu
X
Wang
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Lawren C
LC
Wu
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Zhonghua
Z
Pei
D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase
ITK; Indazole; SBDD; X-ray crystallography; π-stacking