Track: Discovery and Basic Research - Medicinal Chemistry - Small Molecules
Category: Poster Abstract
C1 Analogues Have Improved Anti-Cancer Activity and Accumulation in TNBC Cell Line
Purpose: Sarcoendoplasmic reticulum calcium ATPase (SERCA) is a critical intracellular regulator of Ca+2 which is important for precise protein folding. Perturbation of intracellular Ca+2 can enhance protein misfolding and is upregulated in cancers. To accommodate protein misfolding, cancer cells upregulate unfolded protein response (UPR). Although this is a cancer adaptive mechanism, when UPR exceeds a certain threshold, it also activates pro-apoptotic mechanisms. We have developed a novel anti-cancer compound, C1, a bioavailable specific inhibitor of SERCA2 that is able to selectively inhibit triple negative breast cancer (TNBC) in vitro and in vivo using a xenograft model. C1 also served as a platform for the optimization us and development of more effective compounds. Methods: C1 analogs were identified from a battery of anti-tumor activity assays including cellular viability (MTT assay) and the ability to activate the ER stress pathway using a spectrum of concentration. Pharmacological molecular dissection of analogues was studied used Western Blot analysis of UPR pathways. Using this strategy, we have identified three lead compounds, C8, C9, and C11, that were shown to enhance intracellular accumulation using LCMS analyses. Results: Using C1 as our prototype, we have identified three promising anti-cancer compounds: C8, C9, and C11. C8, C9 and C11 have improved EC 50 of 12.37, 10.15 and 8.60 µM, respectively in TNBC cell line, MDA-MB-231. Cellular accumulation assays of C1 analogues using LCMS showed that C11 is a more potent version of C8, with the same accumulation pattern, but at lower treated concentration in cells. Interestingly, C8 and C9 accumulated in cells exponentially and linearly, respectively. From molecular studies, C11 and C9 were capable of reducing expression of SERCA 2 and increasing expression of GRP78 after 1 hour of treatment. Conclusion: C8, C9, and C11 are improved C1 analogues to treat TNBC. C1 analog dose dependent treatment leads to the increased accumulation of the compound in MDA-MB-231 cell line, but accumulate rate differed depending on the analog. Molecularly, C9 and C11 inhibited the expression of SERCA2 and activated GRP78 upregulation earlier than prototype C1 after 1 hour of treatment. With these properties, C8, C9 and could potentially be an even more effective component in the treatment of TNBC.