Mechanism of action: Phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit beta (PIK3CB; PI3Kb) and delta (PIK3CD; PI3Kd) inhibitor
AZD8186 is a novel potent small molecule that targets the lipid kinase PI3Kβ with selectivity vs PI3Kα. AZD8186 reduces pAKT-(ser473) in the PTEN deficient MDA-MB-468 cell line with an IC50 <5nM, while in the PI3Kα-dependent PIK3CA mutant line BT474 it is 200 fold less potent. AZD8186 also demonstrates cellular activity versus PI3Kd, inhibiting IgM-dependent pAKT-(ser473) with an IC50 of 15nM. In cell line panels, sensitivity to AZD8186 is associated in part with loss of PTEN function suggesting that targeting tumours that have lost normal levels of PTEN function through deletion, mutation or down regulation might enrich for sensitivity to AZD8186. AZD8186 is also able to inhibit signalling downstream of a limited set of GPCRs namely ADP/thrombin, SIP and LPA receptors.
Combining AZD8186 with MDV-3100 resulted in synergistic inhibition of LNCAP prostate tumour cell growth, demonstrating the potential to combine with androgen therapy. Moreover in HCC70 (breast) and PC3 (prostate) tumour xenografts AZD8186 shows increased benefit in combination with docetaxel, demonstrating the ability to combine with cytotoxic chemotherapy.
Safety and tolerability
AZD8186 has been administered orally to a range of cancer patients (CRPC, TNBC, Squamous NSCLC)in single and multiple doses. No clinical dosing limiting adverse effects have yet been observed in the dose escalation phase of the study.
Preclinical studies of up to 1 month duration have been performed.
In vitro studies showed AZD8186 is an inducer of CYP3A4 and to a lesser extent CYP2B6 in human hepatocytes. AZD8186 is a weak inhibitor of CYP2C9. AZD8186 is cleared predominantly by CYP3A4. There is therefore a risk that the PK of AZD8186 may be affected by co-administration with inducers and/or potent inhibitors of CYP3A4.
Suitable for and exclusions
Preclinical toxicology has showed hepatic changes in both mice & dogs. Reproductive changes associated with testicular tubular degeneration were observed. Women of child bearing potential can be included if using adequate contraceptive measures. AZD8186 was shown to inhibit ADP-stimulated platelet aggregation in the dog with no adverse effects on bleeding in vivo. There is a potential phototoxicity risk.
Indications and dosing schedule need to consider use of an intermittent dosing to maximise efficacy and tolerability profile including the need to manage the potential for DDI in this context.
Clinical Trials for this compound
See all of the Clinical Trials currently associated with this compound:
Publications for this compound
Find out more about this compound by reading related Publications:
Molecular Cancer Theraputics
Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel
Gene information from the NCBi
This compound works on the following genes: