A PI3Kβ/δ inhibitor
Description:
IC50: 0.003 μM for PI3Kβ and 0.017 μM for PI3Kδ
The PI3K-Akt signaling pathway plays a critical role in cell growth, proliferation, motility, and survival. In human cancer, this pathway is activated by several mechanisms, including somatic mutations, deletions, and amplifications. Class I PI3Ks are further divided into class IA enzymes (PI3Kα, PI3Kβ, and PI3Kδ) and class IB enzymes (PI3Kγ). AZD8186 is a potent and selective inhibitor of PI3Kβ and PI3Kδ.
In vitro: AZD8186 gave potent inhibition of p-Akt in cells sensitive to PI3Kβ inhibition and in cells sensitive to PI3Kδ inhibition but not to cells sensitive to PI3Kα inhibition. The overall kinase selectivity of AZD8186 was evaluated in several panels of recombinant protein and lipid kinase assays. 13 did not show significant activity against a panel of 59 protein kinases tested at 1 μM [1].
In vivo: The antitumor activity of AZD8186 was evaluated in the PTEN deficient PC3 prostate tumor xenograft model in nude mice, either at 100 mg/kg b.i.d. without ABT coadministration, or at 60, 30, and 10 mg/mg b.i.d. with ABT coadministration. Higher inhibition was seen in the 60 and 30 mg/kg groups with ABT coadministration than in the 100 mg/kg group without ABT coadministration [1].
Clinical trial: AZD8186 was selected as a clinical candidate for treatment of PTENdeficient cancers and has recently entered phase I clinical trials [2].
Reference:
[1] Barlaam B, Cosulich S, Degorce S, Fitzek M, Green S, Hancox U, Lambert-van der Brempt C, Lohmann JJ, Maudet M, Morgentin R, Pasquet MJ, Péru A, Plé P, Saleh T, Vautier M, Walker M, Ward L, Warin N.? Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl -2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers. J Med Chem. 2015 Jan 22;58(2):943-62.
[2] https://clinicaltrials.?gov/ct2/show/NCT01884285?term=AZD8186&rank=1
Cell experiment: | Cells are exposed to AZD8186 at concentrations ranging from 3 to 0.01 μM for 2 hours. Cells are then lysed on ice with a buffer containing 25 mM Tris/HCL pH6.8, 3 mM EDTA, 3 mM EGTA, 50 mM NaF, 2 mM sodium orthovanadate, 270 mM sucrose, 10 mM β-glycerophosphate, 5 mM sodium pyrophosphate, and 0.5% Triton X-100 and protease and phosphatase inhibitors. Lysates are diluted with sample loading buffer, separated on 4% to 12% Bis-Tris Novex gels, transferred onto nitrocellulose membranes, and probed with primary antibodies overnight. After a washing step, membranes are incubated with HRP-tagged secondary antibodies and visualized[1]. |
Animal experiment: | Mice[1] The female CB17 SCID mice ages 6 to 8 weeks are used. HID28 in vivo experiments are performed under contract by Xentech, HID28 tumor fragments (approximately 40 mm3) from donor animals are aseptically implanted subcutaneously in at the level of the interscapular region. Outbred athymic (nu/nu) male mice (HSD: Athymic Nude-Foxn1nu) weighing 18 to 25 g. For all animals studies groups are powered with a minimum of 8 animals per group. AZD8186 is generally formulated once weekly as a suspension in HPMC/Tween and dosed once or twice daily (0 and 6-8 hours). AZD8186 is formulated once weekly either alone in 10% DMSO/60% tri-ethylene glycol (TEG)/30% water for injection (WFI) or in the presence of ABT at 10 mg/mL. For twice daily dosing (0 and 6-8 hours), AZD8186 is co-dosed with ABT at 0 hours and administered alone as the single formulation at 6 to 8 hours. RP-56976 is formulated fresh in physiologic saline at 1.5 mg/mL and dosed as a single i.v. bolus dose at a rate of 0.1 mL/10 g on day 0, 24 hours before the administration of AZD8186. |
参考文献: [1]. Hancox U, et al. Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with RP-56976. Mol Cancer Ther. 2015 Jan;14(1):48-58. | |
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