6-(4-Methyl-1-piperazinyl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(1E)-2-phenylethenyl]-4-pyrimidinamine

Description

ENMD-2076 has selective activity against Aurora A and Flt3 with IC50 of 14 nM and 1.86 nM, 25-fold selective for Aurora A than over Aurora B and less potent to VEGFR2/KDR and VEGFR3, FGFR1 and FGFR2 and PDGFRα. Phase 2.

Features

Multi-target, anti-proliferative, pro-apoptotic activity, anti-angiogenic.

In vitro

ENMD-2076 indicates activity against multiple kinases involved in angiogenesis, including FLT3, RET, FLT4/VEGFR3, SRC, NTRK1, CSF1R/FMS, LCK, VEGFR2/KDR, FGFR1/2, and PDGFRα with IC50 from 1.86-120 nM. ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 μM, which induces apoptosis and G2/M phase arrest. ENMD-2076 induces regression or complete inhibition of tumor growth in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. ENMD-2076 is the L (+) tartrate salt of ENMD-981693. ENMD-2076 shows significant cytotoxicity against myeloma cell lines (IM9, ARH-77, U266, RPMI 8226, MM.1S, MM.1R, NCI-H929) and primary cells with IC50 from 2.99 to 7.06 μM, which induces apoptosis. ENMD-2076 indicates low cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibits the phosphoinositide 3-kinase/Akt pathway and downregulates survivin and X-linked inhibitor of apoptosis. ENMD-2076 also inhibits aurora A and B kinases, and induces G2/M cell cycle arrest.

In vivo

ENMD-2076 has sustained inhibitory effects on the activation of Flt3 as well as VEGFR2/KDR and FGFR1/2 in HT29 xenograft model. ENMD-2076 could prevent the formation of new blood vessels and regress formed vessels in MDA-MB-231 xenograft model. Oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) inhibits the tumour growth in H929 human plasmacytoma xenografts, with significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3.

Biological Activity

enmd-2076 is a selective inhibitor of aurora a and flt3 with ic50 value of 14 and 1.86 nm[1].aurora kinases contains aurora a, aurora b and aurora c. they are serine/threonine kinases witch play an important role in cell proliferation. aurora kinases are essential for cellular division by controlling segregation of chromatid. aurora a is required for correct function of the centrosomes during the prophase of mitosis [1]. vegfr (vegf receptors) are receptors for vegf (vascular endothelial growth factor). there are vegfr 1, 2 and 3 which three main subtypes of vegfr. the vegfrs are tyrosine kinase receptors which are activited by binding to vegfs then mediate the cellular responses to vegf including the formation of the circulatory system (vasculogenesis) and the growth of blood vessels(angiogenesis) [1].enmd-2076 indicates activities of ret, flt3, flt4/vegfr3, src, csf1r/fms, ntrk1, fgfr1/2, vegfr2/kdr, lck, and pdgfrα which all are kinases involved in angiogenes with ic50 from 1.86-120 nm. enmd-2076 can inhibit the growth of hematopoietic cancer cell lines and lots of solid tumor with ic50 values from 25 to 700 nm in vitro[1]. enmd-2076 significantly caused cytotoxicity in multiple myeloma (mm) cell lines and primary cells. enmd-2076 also inhibited the phosphoinositide 3-kinase (pi3k)/akt pathway. enmd-2076 also induced cell cycle arrest in g2/m phase by inhibiting the activities of aurora kinases containing a and b class.[2]enmd-2076 regresses formed vessels and prevents new blood vessels formation in tumorxenograft models. [1] enmd-2076 resulted in inhibition of tumour growth with oral treatment a dose-dependent manner with 50, 100, 200 mg/kg per day with human plasmacytoma xenografts[2].

target

Aurora A

References

[1]. fletcher gc, brokx rd, denny ta, hembrough ta, plum sm, fogler we, sidor cf, bray mr: enmd-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. mol cancer ther 2011, 10(1):126-137.
[2]. wang x, sinn al, pollok k, sandusky g, zhang s, chen l, liang j, crean cd, suvannasankha a, abonour r et al: preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, enmd-2076, against multiple myeloma. br j haematol 2010, 150(3):313-325.