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CAS No. 1007207-67-1
CH5132799 inhibits class I PI3Ks, particularly PI3Kα with IC50 of 14 nM; less potent to PI3Kβδγ, while sensitive in PIK3CA mutations cell lines. Phase 1.
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Effect of selected compounds on MLC phosphorylation induced by 2-AG. Washed platelets (1.0 x 109 platelets/mL) were preincubated at 37 ℃ for 10 min with saline or 20 uM LY294002 (L), 10 uM CH5132799 (C), 10 uM TGX221 (T), 10 uM MK2206 (M), 20 uM Y27632 (Y), 1 uM PIK-75 (P), 1 U/mL apyrase (AP), 5 uM AS252424 (AS), 1 uM IC87114 (IC) and then stimulated for 30 s with 10 uM 2-AG. At the end of incubation suitable aliquots were immunoblotted with anti-p-MLC (thr18/ser19) as detailed in Methods. Blot is representative of four independent experiments.
Biochimie 2014 105, 182-91. CH5132799 purchased from Selleck.
A549 cell was trypsinized and plated at 50% confluence in DMEM. 16 hours later, CH5132799 was added at final concentrations of 0, 1, 5, 10 and 20uM. Another 24 hours later, cells were harvested in RIPA with protease and phosphatase inhibitor cocktail. Total protein concentration was measured by BCA method. Lysates equivalent to 20ug total protein were subject to Western Blot, using total- AKT, pS473-AKT and beta-actin (internal control) antibodies.
CH5132799 purchased from Selleck.
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|Description||CH5132799 inhibits class I PI3Ks, particularly PI3Kα with IC50 of 14 nM; less potent to PI3Kβδγ, while sensitive in PIK3CA mutations cell lines. Phase 1.|
CH5132799 selectively inhibits class I PI3Ks, PI3Kα (IC50 = 0.014 μM ), PI3Kβ (IC50 = 0.12 μM ), PI3Kδ (IC50 = 0.50 μM ), PI3Kγ (IC50 = 0.036 μM ), but shows less inhibition of class II PI3Ks, class III PI3k and mTOR and also no inhibitory activity (IC50 > 10 μM) against 26 protein kinases. CH5132799 exhibits more inhibitory activities against PI3Kα with oncogenic mutations E542K (IC50 = 6.7 nM), E545K (IC50 = 6.7 nM) and H1047R (IC50 = 5.6 nM) than wild-type PI3Kα. CH5132799 treated breast cnacer KPL-4 cells, which harbor the PIK3CA mutation, phosphorylation of Akt and its direct substrates, PRAS40 and FoxO1/3a and phosphorylation of downstream factors, including S6K, S6 and 4E-BP1, are effectively suppressed. Cancer cell lines harboring PIK3CA mutations are significantly sensitive to CH5132799  In human tumor cell lines with PI3K pathway activation by mutation, CH5132799 shows potent antiproliferative activity [HCT116(CRC): IC50 = 0.20 lM, KPL-4(BC):13 IC50 = 0.032 lM, T-47D(BC): IC50 = 0.056 lM, SK-OV-3(Ovarian): IC50 = 0.12 lM]. CH5132799 effectively suppresses phosphorylation of AKT in KPL-4 cells. 
|In vivo||CH5132799 shows potent in vivo antitumor activity in several different xenograft models with PIK3CA mutations. CH5132799 overcomes mTORC1 inhibition-mediated Akt activation and regrowth of xenograft tumor by long-term everolimus administration.  CH5132799 as a clinical candidate that shows excellent oral bioavailability (BA) (101% in mouse), human liver microsomal stability and in vivo antitumor activity in the PC-3 xenograft model (TGI: 101% at 25 mg/kg, po, q.d. × 11 days). CH5132799 exhibits good oral BA in mouse, rat, monkey and dog (F: 54.2-101%). In a human breast cancer (KPL-4: PI3Ka H1047R) xenograft model in mice, oral treatment with CH5132799 (12.5 mg/kg, q.d.) shows strong tumor regression. The strong regression is maintained during the 6 week administration, even in the intermittent dosing schedule (q.d., 2 weeks on/1 week off; q.d., 5 days on/2 days off), suggesting that a flexible administration schedule can be applicable in the clinic. |
PI3K Assay:The E542K, E545K, and H1047R mutants of PI3Kα are prepared with an overlapped extension-polymerase chain reaction. Glutathione S-transferase-tagged PI3Kα mutants and His-tagged p85α are co-expressed with BAC-TO-BAC Baculovirus Expression System. The inhibitory activities of CH5132799 on PI3Kα (p110α/p85α), PI3Kβ(p110β/p85α), PI3Kδ (p110δ/p85α), PI3Kγ (p110γ), PI3KC2α, PI3KC2β, Vps34, and PI3Kα mutants are determined by Adapta Universal Kinase Assay Kit. Time-resolved fluorescence is measured with an EnVision HTS microplate reader. IC50 values are calculated using XLfit.
|In vitro||DMSO||12 mg/mL (31.79 mM)|
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1% DMSO+30% polyethylene glycol+1% Tween 80
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT01222546||Completed||Drug: CH5132799||Solid Tumors||Chugai Pharma Europe Ltd.||August 2010||Phase 1|
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