Abstract 1804: Novel indole compound LX-039 as an oral selective estrogen receptor degrader (SERD) for treating estrogen receptor positive (ER+) breast cancer
Authors: Lu Jianyu , Hu Lihong , Wang Ping , Zhu Yusong , Zou Peng , Wu Dongdong , Ding Charles Z. , Chen Shuhui 
Published: August 2018

Abstract
Objective: Endocrine therapy (ET) now is the standard of care (SOC) for ER+ breast cancer treatment. The representative drug of ET is tamoxifen, a selective estrogen receptor modulator (SERM) that inhibits ER+ breast cancer growth by antagonizing ER function. Tamoxifen displays promising efficacy but also brings problems such as increased endometrial cancer risk and acquired resistance. SERD fulvestrant controls ER+ breast cancer by degrading in-cell ER. It shows improved efficacy in advanced or tamoxifen-resistant (TamR) breast cancer patients and is recently approved as first-line treatment for ER+ breast cancer. However, due to its poor PK profile, this drug could only be administrated intramuscularly, which restricts its applicable patient population. Thus, developing an oral SERD is still an unmet medical need.
Method & Results: We have discovered an oral SERD, LX-039. LX-039 is a novel indole series compound. It robustly degraded ER in MCF-7 breast cancer cells (IC50 = 1.53 nM) and inhibited MCF-7 cell proliferation (IC50 = 2.56 nM). Besides, LX-039 exhibited good PK profile across species, F for mice, rat and dog were 32.2%, 44.5% and 48.1% respectively. Dose to p.o. AUC showed linear relationship, and very high p.o. AUCs could be obtained at high doses. For rat @500 mpk, p.o. AUC reached to 4.52M nM.h, and dog @300 mpk, p.o. AUC reached to 1.5M nM.h. LX-039 displayed promising in vivo antitumor efficacy. In naive MCF-7 breast cancer model, TGI was 87% @ 20 mpk; in TamR MCF-7 model, TGI was 70% @100 mpk. What makes LX-039 more advantageous is its safety profile. LX-039 showed purer ER antagonism. In rat uterine growth inhibition assay, the inhibition rate reached to 94% while inhibition rate of GDC-0810 and AZD-9496 were 65% and 89%, respectively. It had a clean CYP inhibition profile by various CYP assays, which indicates a low DDI risk. LX-039 selectively antagonizes ER without affecting other nuclear receptors such as AR, GR and PR. It showed a clean inhibition profile for a selected kinase/GPCR panel (IC50 &gt;3 μM) and was negative in the GABA gated ion channel assay (IC50 &gt; 10 μM) and the mini Ames test. In the 14 day rat non-GLP tox study, NOAEL of LX-039 was determined to be 300 mpk.
Conclusion: The antitumor efficacy of LX-039 as demonstrated in the preclinical tumor models is highly encouraging and warrants testing the compound in the clinic as an oral SERD for treating ER+ breast cancer. The IND enabling studies of LX-039 are ongoing, and IND filing scheduled in the mid of 2018.
Citation Format: Jianyu Lu, Lihong Hu, Ping Wang, Yusong Zhu, Peng Zou, Dongdong Wu, Charles Z. Ding, Shuhui Chen. Novel indole compound LX-039 as an oral selective estrogen receptor degrader (SERD) for treating estrogen receptor positive (ER+) breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1804.