Abstract B274: Discovery and characterization of a highly selective inhibitor of B-RAF, PI3K, and mTOR kinases with antitumor activity in B-RAF and B-RAF/PI3K pathway double mutant xenograft models.
Authors: Reddy Sanjeeva P. , Jaleel Mahaboobi , Nyavanandi Vijay K. , Ramachandra Murali , Subramanya Hosahalli , Basavaraju Aravind , Sihorkar Vaibhav , Smith Roger A. , Gupta Sandeep , Thompson Scott K. 
Published: August 2014

The RAS-RAF-MAPK and PI3K pathways are two major signaling pathways involved in the initiation and progression of a broad range of tumors. These two pathways are frequently activated in the majority of solid tumors through mutations in various components of the pathways. Inhibition of one pathway often leads to the activation of the other pathway. Preclinical studies have shown that simultaneous inhibition of these two pathways leads to greater efficacy in a broader range of tumor types. For example, despite the presence of the B-RAFV600E mutation, colorectal cancer tumors do not respond to B-RAF selective inhibitors. In contrast, the combination of B-RAF or MEK inhibitors with PI3K pathway inhibitors shows significant tumor growth inhibition in colorectal cancer xenograft models in mice. Currently, there are several clinical trials ongoing using combinations of inhibitors targeting both pathways. We employed a rational drug design approach to discover and develop a single compound with dual inhibition of both RAS-RAF-MAPK and PI3K pathways. EN3352 was identified as a lead compound with potent inhibitory activity against B-RAF, PI3K and mTOR kinases, with low nanomolar IC50 values. Profiling of EN3352 in a panel of 292 kinases showed that it is highly selective for these three kinases. Within the PI3K family, EN3352 is selective for inhibition of PI3Kα versus PI3Kβ. EN3352 showed broader anti-proliferative activity in tumor cell lines compared to the B-Raf selective inhibitors, vemurafenib and dabrafenib. EN3352 has good oral bioavailability in preclinical species and showed inhibition of phosphorylation of the downstream targets of B-RAF, PI3K and mTOR in various tumor models in mice. EN3352 showed regression in a B-RAFV600E mutant A375 xenograft model and also showed significant tumor growth inhibition in a RKO model, which harbors mutations in both B-RAF and PIK3CA genes. Dual targeting of the B-RAF and PI3K pathways with EN3352 has the potential to treat and/or prevent the acquired resistance to selective B-RAF inhibitors, and may also treat a broader patient population and provide greater efficacy and survival benefit than selective B-RAF inhibitors or selective PI3K pathway inhibitors alone.

(Disclosure: Funding for this research was provided by Endo Pharmaceuticals Inc.)

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B274.

Citation Format: Sanjeeva P. Reddy, Mahaboobi Jaleel, Vijay K. Nyavanandi, Murali Ramachandra, Hosahalli Subramanya, Aravind Basavaraju, Vaibhav Sihorkar, Roger A. Smith, Sandeep Gupta, Scott K. Thompson. Discovery and characterization of a highly selective inhibitor of B-RAF, PI3K, and mTOR kinases with antitumor activity in B-RAF and B-RAF/PI3K pathway double mutant xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B274.