Abstract P5-05-09: Cvl218,a second-generation selective parp inhibitors with strong clinical potential for breast cancer
Authors: Shen Xiaokun , Li Zeng 
Published: March 2022

Abstract
CVL218 is a second-generation, potent and selective PARP1/2 inhibitor and now underinvestigated at Ib/II clinical stage in China. Pharmacokinetic studies in rats showed thatCVL218 show best in class tissue distribution profiles and can across the blood-brain barrier (BBB) because of its optimally balanced water-liposolubility, indicating its therapeutic potential in various solid tumors including brain and/or brain metastasis tumor. Besides the superior DMPK properties, CVL218 perform best in class safety dataover the first-generation PARPi in Ia clinical stage which indicates a wider combination usage with other promising therapies such as checkpoint inhibitors and chemotherapies. Here, we report the in vitro and in vivo preclinic outcomes of CVL218 combination usage. These findings suggest that CVL218 is a potential agent for both mono- and combination treatment on various solid tumors including breast cancer.Results:1. PARP enzymes activity, selectivity and solubility CVL218 have a strong potency and better selectivity on PARP1/2 over PARP3/5/6compared with the first-generation PARPi Olaparib and second-generation AZD5305. Furthermore, the Solubility of CVL218 is far more superior than other PARPis. (Table 1) 2. in vitro efficacy of CVL218 combination on breast cancer cell lines In vitro cell-based studies implied that CVL218 could sensitizing the cell proliferation. inhibition of chemotherapies including Taxol and Temozolomide (TMZ) on HRDnegative solid tumors such as breast cancer cell lines, indication the potential for combination use (Table 2). Since TMZ is the first-line drug for treating glioma, CVL218 is also expected for positive outcomes in further clinical trials.(Table 2) 3. Xenograft study of CVL218 combi with checkpoint inhibitorCVL218 was tested alone with PD-1 inhibitor geptanolimab on MDA-MB-436 breast cancer CDX model (NCG, PMBC Humanized, N=10). Formonotherapy, CVL218 (40mpk) was more potent than geptanolimab (10 mpk). WhenCVL218 in combination with geptanolimab, significate tumor growth inhibition was presented compared with PD-1 monotherapy (p&lt;0.01). Moreover, CVL218 possessed very promising safety profiles in both monotherapy and combination therapy. Among all groups, no animal was dead for drug toxicity. The results indicate a very promising prospect for the use of CVL218 combi with checkpoint inhibitor. Conclusions:. CVL218 is a second-generation PARP1/2 inhibitor with strong potency, selectivity,outstanding drug-like properties and very promising safety profiles. In vivo data reveal optimistic expectations for the clinical development of combination usage of CVL218 with chemotherapy and checkpoint inhibitor on solid tumors such as breast cancer. Now Ib/IIclinic trials of CVL218 on solid tumors is conducted in China and combination therapy with chemotherapy and checkpoint inhibitor are expected to start in later 2021.
Table 1.PARP enzymes activity, selectivity and solubilityPARPsCVL218CVL218OlaparibOlaparibAZD5305AZD5305IC50 (nM)FoldIC50 (nM)FoldIC50 (nM)FoldPARP13.21.001.11.003.01.00PARP21.90.590.90.82&gt;1.4&gt;466PARP3&gt;10000&gt;3125258234.5534001133TNKS11600500.0014.5–&gt;89000&gt;29666TNKS21300406.255.9–––PARP6&gt;10000&gt;312515001363.64260008666Solubility35 mg/mL&lt;0.01 mg/mL~ 0.02 mg/mL
Citation Format: Xiaokun Shen, Zeng Li. Cvl218,a second-generation selective parp inhibitors with strong clinical potential for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-09.