XL765

XL765 is a potent inhibitor of PI3Ks with IC50 values 39, 113,43,9 nM for p110α, β, δ, γ and 190, 908 nM for mTORC1, and mTORC2 respectively. [1]
The phosphoinositide-3 kinase (PI3K) pathway has been identified as an important target in breast cancer research. The PI3K pathway is integral to diverse cellular activities, including cellular metabolism and proliferation, survival, and differentiation. Besides, mTOR also acts as the nexus of signaling pathways regulating cell growth and proliferation. By inhibiting these targets, XL765 is thought to contribute to resistance to a variety of anticancer therapies. [2]
XL765 inhibits all four class I PI3K isoforms and mTOR with IC50 values in the nanomolar range in biochemical assays, whereas is highly selective against a panel of over 130 other human kinases. XL765 exhibits inhibition of PI3K-dependent production of the second messenger PIP3, and mTOR-dependent signaling stimulated by nutrient in cellular assays. Moreover, XL765 inhibits PI3K and mTOR-dependent phosphorylation of key components in the PI3K pathway including AKT, the substrates of AKT PRAS40 and GSK3β, p70S6K, the p70S6K substrate S6, and 4E-BP1 in diverse cancer cells. [1,3]
Treatment of XL765 to mice bearing xenografts of PIK3CA mutant MCF-7 breast adenocarcinoma cells or PTEN-deficient PC-3 prostate adenocarcinoma cells resulted in significant inhibition of PI3K and mTOR signaling. XL765 significantly decreased tumor growth or caused tumor shrinkage in different xenograft tumor models, including brain, lung, breast, ovarian, and prostate cancers which were correlated with inhibition of tumor cell proliferation and tumor angiogenesis, and with induction of apoptosis. However, rapamycin inhibited proliferation caused little or no induction of apoptosis. These results demonstrate that a dual inhibitor strategy, targeting both PI3K and mTOR, may offer significant advantages over specifically targeting the mTOR/Raptor complex. XL765 is currently undergoing a Phase I clinical trial in patients with solid tumors.[3]
References:
1.Braña I, LoRusso P, Baselga J, et al. A Phase 1 dose-escalation study of the safety, pharmacokinetics and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients with advanced malignancies[J]. bid, 2010, 16: 5.
2.Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer[J]. The oncologist, 2011, 16(Supplement 1): 12-19.
3.Laird A D. XL765 targets tumor growth, survival, and angiogenesis in preclinical models by dual inhibition of PI3K and mTOR[J]. Molecular Cancer Therapeutics, 2007, 6(11 Supplement): B250-B250.

Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models.[Pubmed:26219891]

Tumour Biol. 2016 Jan;37(1):341-51.

Deregulation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway contributes to prostate cancer development and progression. Here, we compared the in vitro effects of the dual PI3K/mTOR inhibitor (XL765) with those observed with the sole PI3K (XL147) or mTOR (rapamycin) inhibition in 2 non-tumor prostate epithelial cell lines, 8 prostate cancer cell lines, and 11 prostate cancer cell derivatives. We demonstrated that the XL765 treatment showed superior and proliferative effects of XL147 or rapamycin. The XL765 effects were associated to increasing the chromosome region maintenance 1 (CRM1)-mediated nuclear localization of glycogen synthase kinase 3 beta (GSK3beta) and Foxo-1a with higher induction of apoptosis when compared to those observed in XL147 and rapamycin treatments. IC50 values were calculated in phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-positive and PTEN-negative cell lines as well as after PTEN transfection or PTEN downmodulation by siRNA strategy revealing that the presence of this protein was associated with reduced sensitivity to PI3K and mTOR inhibitors. The comparison of IC50 values was also calculated for androgen-dependent and -independent cell lines as well as after androgen receptor (AR) transfection or the AR downmodulation by siRNA strategy revealing that androgen independence was associated with enhanced responsiveness. Our results provide a rationale to use the dual PI3K/Akt/mTOR inhibitors in hormone-insensitive prostate cancer models due to the overactivity of PI3K/Akt/mTOR in this disease condition.

The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells.[Pubmed:26338274]

Leukemia. 2016 Feb;30(2):337-45.

The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3Kdelta block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3Kdelta inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells--irrespective of their ATM/p53 status--than PI3Kalpha or PI3Kdelta isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients.

Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma.[Pubmed:26019185]

Neuro Oncol. 2015 Sep;17(9):1275-83.

BACKGROUND: This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma. METHODS: Patients received voxtalisib 30-90 mg once daily (q.d.) or 20-50 mg twice daily (b.i.d.), in combination with 200 mg/m(2) TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m(2) TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response. RESULTS: The maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade >/=3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%. CONCLUSIONS: Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition.