title: Inhibition of hematopoietic protein tyrosine phosphatase augments and prolongs ERK1/2 and p38 activation.
abstract: The hematopoietic protein tyrosine phosphatase (HePTP) is implicated in the development of blood cancers through its ability to negatively regulate the mitogen-activated protein kinases (MAPKs) ERK1/2 and p38. Small-molecule modulators of HePTP activity may become valuable in treating hematopoietic malignancies such as T cell acute lymphoblastic leukemia (T-ALL) and acute myelogenous leukemia (AML). Moreover, such compounds will further elucidate the regulation of MAPKs in hematopoietic cells. Although transient activation of MAPKs is crucial for growth and proliferation, prolonged activation of these important signaling molecules induces differentiation, cell cycle arrest, cell senescence, and apoptosis. Specific HePTP inhibitors may promote the latter and thereby may halt the growth of cancer cells. Here, we report the development of a small molecule that augments ERK1/2 and p38 activation in human T cells, specifically by inhibiting HePTP. Structure-activity relationship analysis, in silico docking studies, and mutagenesis experiments reveal how the inhibitor achieves selectivity for HePTP over related phosphatases by interacting with unique amino acid residues in the periphery of the highly conserved catalytic pocket. Importantly, we utilize this compound to show that pharmacological inhibition of HePTP not only augments but also prolongs activation of ERK1/2 and, especially, p38. Moreover, we present similar effects in leukocytes from mice intraperitoneally injected with the inhibitor at doses as low as 3 mg/kg. Our results warrant future studies with this probe compound that may establish HePTP as a new drug target for acute leukemic conditions.
authors: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, United States.
authors: Eduard
authors: E
authors: Sergienko
authors: Jian
authors: J
authors: Xu
authors: Wallace H
authors: WH
authors: Liu
authors: Russell
authors: R
authors: Dahl
authors: David A
authors: DA
authors: Critton
authors: Ying
authors: Y
authors: Su
authors: Brock T
authors: BT
authors: Brown
authors: Xochella
authors: X
authors: Chan
authors: Li
authors: L
authors: Yang
authors: Ekaterina V
authors: EV
authors: Bobkova
authors: Stefan
authors: S
authors: Vasile
authors: Hongbin
authors: H
authors: Yuan
authors: Justin
authors: J
authors: Rascon
authors: Sharon
authors: S
authors: Colayco
authors: Shyama
authors: S
authors: Sidique
authors: Nicholas D P
authors: ND
authors: Cosford
authors: Thomas D Y
authors: TD
authors: Chung
authors: Tomas
authors: T
authors: Mustelin
authors: Rebecca
authors: R
authors: Page
authors: Paul J
authors: PJ
authors: Lombroso
authors: Lutz
authors: L
authors: Tautz
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008958:Models, Molecular; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases