Browsing by Author "Mali, Raghuveer S."

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    PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML
    (American Society of Hematology, 2014-05-01) Goodwin, Charles B.; Li, Xing Jun; Mali, Raghuveer S.; Chan, Gordon; Kang, Michelle; Liu, Ziyue; Vanhaesebroeck, Bart; Neel, Benjamin G.; Loh, Mignon L.; Lannutti, Brian J.; Kapur, Reuben; Chan, Rebecca J.; Department of Pediatrics, IU School of Medicine
    Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, the PI3K-Akt signaling pathway is also dysregulated in this disease. Using genetic models, we demonstrate that inactivation of phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110δ, but not PI3K p110α, corrects gain-of-function (GOF) Shp2-induced granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110δ-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK) inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110δ-specific inhibitor, idelalisib, also demonstrates activity against primary leukemia cells from individuals with JMML. These findings suggest that selective inhibition of the PI3K catalytic subunit p110δ could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110δ.
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    Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase
    (American Chemical Society, 2014-08-14) Zeng, Li-Fan; Zhang, Ruo-Yu; Yu, Zhi-Hong; Li, Sijiu; Wu, Li; Gunawan, Andrea M.; Lane, Brandon S.; Mali, Raghuveer S.; Li, Xingjun; Chan, Rebecca J.; Kapur, Reuben; Wells, Clark D.; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    , The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the β5–β6 loop contribute to 11a-1’s binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines.