Activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as TNK2, tyrosine kinase non-receptor 2) binds to multiple receptor tyrosine kinases e.g. EGFR, MERTK, AXL, HER2 and insulin receptor (IR). ACK1 also interacts with Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs.
ACK1 has been shown to interact with AKT, Androgen receptor or AR, tumor suppressor WWOX, FYN and Grb2. ACK1 has been shown to be critical for progression of PC to hormone therapy insensitive stage called castration resistant prostate cancer or CRPC due to it’s ability to regulate the expression and function of AR in androgen-independent manner.
The ACK1 inhibitor (R)-9bMS sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth.
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2. Mahajan K, et al. Cancer Cell. 2017 Jun 12;31(6):790-803.e8.
3. Wu X, et al. Oncotarget. 2017 Jan 10;8(2):2971-2983.
4. Jiao X, et al. Bioorg Med Chem Lett. 2012 Oct 1;22(19):6212-7.
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XMD16-5 is a potent Ack1 (TNK2) inhibitor with IC50 of 0.38 uM in ELISA assay; exhibits potent inhibition of growth of the TNK2 mutant expressing cell lines with IC50s of 16 nM and 77 nM for the D163E and R806Q mutations.
XMD8-87 (Ack1 inhibitor B19) is a potent Ack1 inhibitor with Kd of 15 nM, inhibits EGF-induced autophosphorylation in HEK293 cells at 2 uM; completely inhibits A549 cancer cell growth, and partially inhibited EGF-stimulated cancer cell growth at 10 uM; XMD8-87 is a potent, selective Ack1 (TNK2) inhibitor with IC50 of 1.9 uM in ELISA assays; potently block proliferation of TNK2 mutant cell lines, shows IC50s of 38 nM and 113 nM for the D163E and R806Q mutations.
AIM-100 (AIM100) is a highly potent inhibitor of Ack1 (TNK2) (IC50=24 nM), selective for Ack1 over ABL1, BTK, Lck and LYN; inhibits Ack1 Tyr284-phosphorylation attenuated pTyr267-AR transcriptional activity which in turn resulted in cell cycle arrest; inhibits pTyr284 -Ack1 expression, and prostate cancer cell proliferation.
Ack1 inhibitor (R)-9b is a potent and selective ACK1 (TNK2) inhibitor with IC50 of 48 nM; also inhibits JAK2 (IC50=6 nM) and Tyk2 (IC50=5 nM), 3-fold selectvity over ALK and 10-fold over c-Src; potently suppresses proliferation of human cancer cell lines with IC50 <2 uM; exhibits considerable stability in human plasma and a long half-life.
Ack1 inhibitor 37
Ack1 inhibitor 37 is a potent and selective Ack1 (TNK2) inhibitor with Ki of 0.3 nM, displays high selectivity over related kinases LCK, JAK3, KDR and TIE2 (Ki= 138, 6.5, 380 and 200 nM); demonstrates cell IC50 of 10 nM in cellular autophosphorylation assays, displays excellent ACK1 cellular inhibition, good kinase selectivity, and a suitable in vitro metabolic profile.
(R)-9bMS is a potent and selective ACK1 (TNK2) inhibitor with IC50 of 48 nM; also inhibits JAK2 (IC50=6 nM) and Tyk2 (IC50=5 nM), 3-fold selectvity over ALK and 10-fold over c-Src; potently suppresses proliferation of human cancer cell lines with IC50 <2 uM; exhibits considerable stability in human plasma and a long half-life.
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