Synthesis and Biological Evaluation of Novel Analogues of the Pan Class I Phosphatidylinositol 3-Kinase (PI3K) Inhibitor 2-(Difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1<i>H</i>-benzimidazole (ZSTK474)

Rewcastle, Gordon W.; Gamage, Swarna A.; Flanagan, Jack U.; Frédérick, Raphaël; Denny, William A.; Baguley, Bruce C.; Kestell, Philip; Singh, Ripudaman; Kendall, Jackie D.; Marshall, Elaine S.; Lill, Claire L.; Lee, Woo Jung; Kolekar, Sharada; Buchanan, Christina M.; Jamieson, Stephen M.F.; Shepherd, Peter R.

doi:10.1021/jm200688y

Cited by 98 publications

(56 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional evidence that PI3K is required for NK CMC has emerged from genetic and pharmacological inhibition of the PI3K isoforms p110γ or p110δ [24], [26]–[30]. To confirm the PI3K-dependence of NK cell functions under our experimental conditions, we used the selective pan-class I inhibitors ZSTK474 [31], [32] and GDC-0941 [33]–[35]. As shown in Table 1 , both compounds inhibit all four class I PI3K enzymes in the low to mid-nanomolar range in vitro ; in cellular assays these compounds block PI3K signaling selectively when used at 0.1–1 µM.…”

Section: Resultsmentioning

confidence: 99%

Effects of Novel Isoform-Selective Phosphoinositide 3-Kinase Inhibitors on Natural Killer Cell Function

Yea

Mallya

et al. 2014

PLoS ONE

View full text Add to dashboard Cite

Phosphoinositide 3-kinases (PI3Ks) are promising targets for therapeutic development in cancer. The class I PI3K isoform p110α has received considerable attention in oncology because the gene encoding p110α (PIK3CA) is frequently mutated in human cancer. However, little is known about the function of p110α in lymphocyte populations that modulate tumorigenesis. We used recently developed investigational inhibitors to compare the function of p110α and other isoforms in natural killer (NK) cells, a key cell type for immunosurveillance and tumor immunotherapy. Inhibitors of all class I isoforms (pan-PI3K) significantly impaired NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity against tumor cells, whereas p110α-selective inhibitors had no effect. In NK cells stimulated through NKG2D, p110α inhibition modestly reduced PI3K signaling output as measured by AKT phosphorylation. Production of IFN-γ and NK cell-derived chemokines was blocked by a pan-PI3K inhibitor and partially reduced by a p110δinhibitor, with lesser effects of p110α inhibitors. Oral administration of mice with MLN1117, a p110α inhibitor in oncology clinical trials, had negligible effects on NK subset maturation or terminal subset commitment. Collectively, these results support the targeting of PIK3CA mutant tumors with selective p110α inhibitors to preserve NK cell function.

show abstract

Section: Resultsmentioning

confidence: 99%

Effects of Novel Isoform-Selective Phosphoinositide 3-Kinase Inhibitors on Natural Killer Cell Function

Yea

Mallya

et al. 2014

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…A66 (36), ZSTK474 (37), BEZ235 (38), TGX-221, and AS-252424 (39) were synthesized at the Auckland Cancer Society Research Centre as previously described. Selumetinib (Selleck Chemicals and LC Laboratories), vemurafenib (Medkoo Biosciences), idelalisib (Symansis), and KU-0063794 (Selleck Chemicals) were supplied as indicated.…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth

et al. 2015

Self Cite

View full text Add to dashboard Cite

BRAF and MEK inhibitors have improved outcomes for patients with BRAF-mutant melanoma, but their efficacy is limited by both intrinsic and acquired resistances. Activation of the PI3K pathway can mediate resistance to these agents, providing a strong rationale for combination therapy in melanoma. Here, a panel of nine low-passage human metastatic melanoma cell lines with BRAF mutations was tested in cell proliferation and protein expression assays for sensitivity to inhibitors of MEK (selumetinib) and BRAF (vemurafenib) as single agents and in combination with inhibitors of pan-PI3K (ZSTK474), pan-PI3K/mTOR (BEZ235), individual PI3K isoforms (p110α, A66; p110β, TGX-221; p110γ, AS-252424; p110δ, idelalisib), or mTORC1/2 (KU-0063794). Selumetinib and vemurafenib potently inhibited cell proliferation in all cell lines, especially in those that expressed low levels of phosphorylated AKT (pAKT). ZSTK474 and BEZ235 also inhibited cell proliferation in all cell lines and enhanced the antitumor activity of selumetinib and vemurafenib in the majority of lines by either interacting synergistically or additively to increase potency or by inducing cytotoxicity by significantly increasing the magnitude of cell growth inhibition. Furthermore, ZSTK474 or BEZ235 combined with selumetinib to produce robust inhibition of pERK, pAKT, and pS6 expression and synergistic inhibition of NZM20 tumor growth. The inhibitors of individual PI3K isoforms or mTORC1/2 were less effective at inhibiting cell proliferation either as single agents or in combination with selumetinib or vemurafenib, although KU-0063794 synergistically interacted with vemurafenib and increased the magnitude of cell growth inhibition with selumetinib or vemurafenib in certain cell lines. Overall, these results suggest that the sensitivity of BRAF-mutant melanoma cells to BRAF or MEK inhibitors is at least partly mediated by activation of the PI3K pathway and can be enhanced by combined inhibition of the BRAF/MEK and PI3K/mTOR signaling pathways.

show abstract

“…We used IC87114 as a p110␦ inhibitor (27)(28)(29). To inhibit all class I isoforms, we used the two compounds GDC-0941 (11,30,31) and ZSTK474 (32,33). In vitro, both compounds inhibit all class I isoforms with IC 50 values between 3 and 75 nM with some preference for p110␣ and p110␦ (Table 1).…”

Section: Pi3kmentioning

confidence: 99%

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

Yea

Oak

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The class IA PI3K isoform p110␣ is a promising drug target in cancer therapy yet its role in lymphocytes is not known. Results: Lymphocyte function was minimally affected by p110␣ inhibition both in vitro and in vivo. Conclusion: Selective inhibition of p110␣ preserves lymphocyte function. Significance: The study raises confidence that selective p110␣ inhibitors in cancer therapy will not be immunosuppressive.

show abstract

Synthesis and Biological Evaluation of Novel Analogues of the Pan Class I Phosphatidylinositol 3-Kinase (PI3K) Inhibitor 2-(Difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474)

Cited by 98 publications

References 61 publications

Effects of Novel Isoform-Selective Phosphoinositide 3-Kinase Inhibitors on Natural Killer Cell Function

Effects of Novel Isoform-Selective Phosphoinositide 3-Kinase Inhibitors on Natural Killer Cell Function

Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

Contact Info

Product

Resources

About