Abstract 1239: Putative Bax activators GL0385 and GL0388 for targeted breast cancer therapy
Authors: Fricke Doerte R. , Kim Hyejin , Liu Gang , Chen Haiying , Zhou Jia , Shen Qiang 
Published: July 2021

Breast cancer is one of the leading causes of cancer-related death in American women and the most common cancer in women with more than 270,000 estimated new cases in 2020 in the US. This is about 30% of the estimated total cancer patients in American women and therefore a major threat to the society with an urgent need of advanced treatment regimens. Especially the subgroup of estrogen receptor (ER)-negative breast cancers (ENBC), which are approximately one quarter to a third of all breast cancer, are lacking efficient treatment methods. Particularly dangerous is triple-negative breast cancer (TNBC), a subtype of ENBC with a high metastatic potential, since 90% of cancer-related deaths are due to metastasis. However, an effective drug for ENBC/TNCB treatment remains to be developed. The pro-apoptotic protein Bax was shown to be downregulated in most cancers. As a result, the balance between Bax and its antagonist Bcl-2 gets disturbed which leads to dysfunctional apoptotic signaling in favor of cancer cell survival. Upon activation, Bax is translocated from the cytosol to the mitochondria where it binds to the outer mitochondrial membrane. This leads to increased permeability of the mitochondrial membrane and a release of pro-apoptosis related molecules such as cytochrome C and others. Hence, drug discovery for Bax activation is a promising approach for developing novel cancer therapies. The small molecules GL0385 and GL0388 were identified from our progenitor molecules including small-molecule Bax activator (SMBA1), CYD-2-11, and CYD-4-61. The CYD compounds specifically target the Ser184 residue of Bax and have shown apoptosis-inducing effects both in vitro and in vivo. These lead Bax activators provided proof-of-concept studies while further optimization is needed to mitigate potential toxicity, leading to the discovery of advanced lead molecules GL0385 and GL0388. Treatment with either GL0385 or GL0388 resulted in significantly decreased cell proliferation in MDA-MB-231, MDA-MB-468, BT549, MDA-MB-453, MCF-7, and MDA-MB-361 cells. Additionally, MDA-MB-231 cells treated with GL0385 or GL0388 showed reduced migration and invasion, compared to control cells. Western blot analysis confirmed increased protein levels of Bax, cleaved PARP, cleaved caspase 3, and cytochrome C. These results show that GL0385 and GL388 have a significant impact on cancer cell proliferation and cellular motility which are main attributes of metastasizing cells. Additionally, increased expression of apoptosis markers indicates that these compounds may be beneficial to regain the anti-apoptotic/pro-apoptotic balance in breast cancer cells. Therefore, GL0385 and GL0388 are promising new advanced lead compounds towards the development of effective therapies for breast cancers and other cancers. Further investigation is warranted to fully explore their anti-cancer potential and mechanisms of action.

Citation Format: Doerte R. Fricke, Hyejin Kim, Gang Liu, Haiying Chen, Jia Zhou, Qiang Shen. Putative Bax activators GL0385 and GL0388 for targeted breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1239.