Abstract 3258: Discovery and characterization of SAR260301, a novel PI3Kβ-selective inhibitor in clinical development for the treatment of PTEN-deficient tumors .

Abstract

The PI3K/mTOR pathway is involved in promoting tumor cell proliferation, survival and metastasis. The development of new anticancer therapies targeting different components of this pathway has been motivated by the identification of somatic PIK3CA missense mutations as well as the high frequency of loss of negative regulatory proteins such as the tumor suppressor PTEN. In this last case, the abnormal activation of downstream effectors is mediated by PI3Kβ. PTEN deficiency has also been reported to be involved in the resistance to a variety of anticancer therapies. The preceding findings support investigation into selective modulators of the lipid kinase activity of p110β as agents for the treatment of PTEN-deficient tumors, with potentially reduced on-target adverse events described for pan-PI3K inhibitors currently undergoing clinical trials. SAR260301 is a selective PI3Kβ lipid kinase inhibitor that has demonstrated higher potency in vitro on p110β (IC50= 52 nM) than on p110δ and p110α isoforms and no or weak activity against p110γ, mTOR and a wide range of protein kinases (>400 enzymes). The potency and selectivity against the intended target was further confirmed in mechanistic cellular models (IC50 = 32 nM, p110β; 26- and 88-fold selective over p110δ and p110α, respectively). Moreover, SAR260301 also modulates pAkt levels exclusively in PTEN-deficient tumor cell lines with IC50 values ranging from 39 to 310 nM and from 20 to 209 nM for pAkt-S473 and pAkt-T308, respectively. When administered orally, the compound shows dose and time-dependent inhibition of the PI3K pathway in human PTEN-deficient tumor xenografts in mice. In these models, target engagement correlates with compound exposure and is associated with good tolerability. The MAPK pathway also plays an important role in cancer and is often constitutively and simultaneously activated with the PI3K pathway. Furthermore, PTEN loss has been shown to correlate with resistance to MAPK inhibitors. Preclinical data evidencing the ability of SAR260301 to modulate pAkt levels in genetic contexts where PTEN deficiency co-exists with MAPK pathway activation, as well as the effects of combining SAR260301 with MAPK inhibitors will also be presented. The foregoing studies support ongoing Phase I clinical investigation of SAR260301 in patients with PTEN-deficient malignancies. Citation Format: Angela Virone-Oddos, Hélène Bonnevaux, Olivier Lemaitre, Loic Vincent, Franck Halley, Brigitte Demers, Véronique Charrier, Olivier Courtin, Stéphane Guérif, Laurent Besret, Pierre-Yves Abecassis, Sylvaine Cartot-Cotton, Gary Emmons, Alan Roberts, David Compton, Bin Wu, Laurent Schio, Christoph Lengauer, Carlos Garcia-Echeverria. Discovery and characterization of SAR260301, a novel PI3Kβ-selective inhibitor in clinical development for the treatment of PTEN-deficient tumors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3258. doi:10.1158/1538-7445.AM2013-3258

Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients

“…Selective p110b inhibitors include GSK2636771 (GlaxoSmithKline, Brentford, UK) and SAR260301 (Sanofi, Paris, France), which are currently in early-phase clinical trials [95,96], and AZD8186 (AstraZeneca, London, UK). Administration of AZD8186 as a single agent or in combination with docetaxel both resulted in inhibition of PTEN-deficient breast and prostate tumor growth [97].…”

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

“…All these results have fueled a renewed interest in the area of PI3K isoform selective inhibitors, including PI3Kβ selective inhibitors. Recently, many PI3Kβ selective inhibitors − have been disclosed, including 2-methyl-1-[2-methyl-3-(trifluoromethyl)benzyl]-6-(morpholin-4-yl)-1 H -benzimidazole-4-carboxylic acid (GSK2636771) and 5 (SAR260301), , which are in early clinical trials.…”

Immunotherapies targeting stimulatory pathways and beyond

“…SAR260301 is a selective inhibitor of PI3Kβ and has been effective in cancers with PTEN deficiency. Loss of PTEN, a tumor suppressor protein, leads to PI3Kβ upregulation [ 123 ]. SAR260301 is being evaluated as monotherapy in a phase I clinical trial in patients with advanced solid tumors (NCT01673737).…”