XL765 (Synonyms: SAR245409; XL-765;SAR 245409;SAR- 245409)

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.