Profile of buparlisib and its potential in the treatment of breast cancer: evidence to date

Abstract

Alteration of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is key for the growth and survival of several cancers, including breast cancer. In addition, dysregulation of PI3K signaling may contribute to resistance to several anticancer agents. PI3K inhibitors may, therefore, be effective as antineoplastic therapy. Buparlisib is a potent and highly specific oral inhibitor of the pan-class I PI3K family. Buparlisib specifically inhibits class I PIK3 in the PI3K/AKT kinase signaling pathway in an ATP-competitive manner, thus inhibiting the production of the secondary messenger phosphatidylinositol (3,4,5)-trisphosphate and activation of the PI3K signaling pathway. This may induce inhibition of tumor cell growth and survival in susceptible tumor cell populations. Buparlisib is currently under investigation in patients with a variety of solid tumors, including breast cancer. Buparlisib has been validated as a promising anticancer agent, and tremendous efforts have been taken to develop it. However, buparlisib monotherapy has resulted in humble benefit so far. Results from studies combining buparlisib with different anticancer agents – namely, endocrine therapy, anti-HER2 therapy, and chemotherapy – have showed variable efficacy with consistent substantial toxicity.

Micellar Formulation of Talazoparib and Buparlisib for Enhanced DNA Damage in Breast Cancer Chemoradiotherapy

“…[11][12][13] In fact, the biological role of these proteins has inspired many clinical PI3K inhibitor-drug combination trials in order to overcome resistance and enhance chemotherapeutic efficacy. 14 In particular, utilizing the PI3K inhibitor buparlisib (Bup) sensitized cells to PARP inhibition by reducing BRCA expression. 12,[15][16][17] In this way, administering a PI3K inhibitor to mimic BRCA mutated cancer revitalizes PARP therapy for a large subset of patients, previously unresponsive to PARP inhibition.…”

Discovery, Synthesis, and Scale-up of Efficient Palladium Catalysts Useful for the Modification of Nucleosides and Heteroarenes

“…This work provided easy access to molecules such as Buparlisib intermediate (Scheme 12). Buparlisib is an important drug candidate exhibiting pan-PI3K inhibitor activity that is under clinical development, especially for brain tumor treatment [67]. This protocol also offered significant improvement in the yield over the previously reported methods for the amination of 6-chloropurine riboside providing 6-N-substituted adenosine analogues exhibiting promising applications in pharmacology and biochemistry (Scheme 13) [42].…”

“…This work provided easy access to molecules such as Buparlisib intermediate (Scheme 12). Buparlisib is an important drug candidate exhibiting pan-PI3K inhibitor activity that is under clinical development, especially for brain tumor treatment [67].…”

Current and Investigational Agents Targeting the Phosphoinositide 3‐Kinase Pathway

“…The IC 50 of buparlisib at PI3K α, β, γ, and δ is 52, 166, 262, and 116 nmol/L, respectively . Early preclinical data suggested that buparlisib may have off‐target effects including antimicrotubular and antiangiogenic effects; however, these data are unlikely to provide clinically significant contributions because the doses and concentrations seen in clinical studies are much lower following the identification of an MTD …”