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Structure‐Function Correlation of G6, a Novel Small Molecule Inhibitor of Jak2: Indispensability of the Stilbenoid Core
Author(s) -
Majumder Anurima,
Govindasamy Lakshmanan,
Magis Andrew,
Kiss Robert,
Polgar Timea,
Allan Robert W.,
AgbandjeMcKenna Mavis,
Keseru György M.,
Bisht Kirpal,
Sayeski Peter P.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.620.5
Subject(s) - stat5 , chemistry , small molecule , cell growth , cancer research , apoptosis , phosphorylation , in vivo , janus kinase 2 , ex vivo , stat3 , microbiology and biotechnology , biochemistry , in vitro , biology , genetics
Somatic mutations in the Jak2 allele, such as V617F, cause aberrant Jak‐STAT signalling and can lead to the development of myeloproliferative neoplasms (MPNs). This has led to the search for small molecule inhibitors that target Jak2. Using structure‐based virtual screening, our lab recently identified a novel small molecule inhibitor of Jak2 named G6. Here, we identified a structure‐function correlation of this compound. Specifically, five derivative compounds of G6 having structural similarity to the original lead compound were analyzed for their ability to i) inhibit Jak2‐V617F mediated cell growth ii) inhibit the levels of phospho‐Jak2, phospho‐STAT3 and phospho‐STAT5 iii) induce apoptosis in HEL cells and iv) suppress pathologic cell growth of Jak2‐V617F expressing human bone marrow cells, ex vivo . Additionally, we examined the interactions of these compounds with the ATP binding pocket of the Jak2 kinase domain. We found that the stilbenoid core containing derivatives of G6 significantly inhibited Jak2‐V617F mediated cell proliferation in a time‐ and dose‐dependent manner. They also inhibited phosphorylation of Jak2, STAT3 and STAT5 proteins within cells. Moreover, we report that these stilbenoid derivatives of G6 induced apoptosis and inhibited the pathologic growth of Jak2‐V617F expressing human bone marrow cells, ex vivo . Collectively, our data demonstrate that G6 has a core stilbene structural element which is indispensable for maintaining its Jak2 inhibitory potential. Supported by R01‐HL67277.