Abstract A225: Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through structural optimization.

Abstract

Abstract Multiple myeloma (MM) is an incurable malignancy of plasma cells, which is associated with the overactivated phosphatidylinositol 3-kinases (PI3Ks)/AKT signaling pathway. Stimulated by interleukin 6 and or insulin-like growth factor 1, PI3K/AKT plays a key role in MM survival and chemoresistance, while genetic knockdown of these PI3-kinases by small interfering RNA (siRNA) leads to MM cell apoptosis and decreased proliferation. Therefore, PI3K is granted as a promising therapeutic target for MM. We previously identified the small molecule compound S14161 an inhibitor of pan-Class I PI3K isoforms by a high throughput screening strategy (Mao et al., 2011). S14161 displayed potent preclinical activity against MM and leukemia in vitro and in vivo. In the present study, we synthesized a panel of S14161 analogs based on the structure-activity relationship, of which BENC-511 was demonstrated to be more potent than S14161 in suppressing PI3K activity and inducing MM cell death. BENC-511 was derived from S14161 by removing 4-fluorophenyl group at the 2-position of the chromene core. Different from S14161, BENC-511 presented as a specific inhibitor for PI3K α and δ, but had no inhibitory effects on PI3K β, γ, AKT, or mTOR in the cell-free enzymatic assays. BENC-511 inhibited phosphorylation of AKT and its downstream signals mTOR, P70S6K, and 4E-BP-1 at low micromolar concentrations. Consistent with its effects on PI3K activity and cancer cell proliferation, BENC-511 induced MM cell apoptosis. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death. BENC-511 also showed potent anti-myeloma activity in vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis. Because of its robust potential and low toxicity (LD50 oral >1.5 g/kg), BENC-511 could be developed as a promising agent for the treatment of multiple myeloma by targeting the PI3K/AKT signaling pathway. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A225. Citation Format: Kunkun Han, Xin Xu, Guodong Chen, Yuanying Zeng, Jingyu Zhu, Xiaolin Du, Zubin Zhang, Biyin Cao, Zhaopeng Liu, Xinliang Mao. Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through structural optimization. [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 A225.