In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4844-4844
Abstract:
The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (Rb) pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib have been approved by US FDA as single agent or in combination with endocrine therapy to treat patients with HR+/Her2- breast cancer. Here, we disclose the preclinical development of CS3002 and its characterization as a novel CDK4/6 inhibitor with unique kinase inhibition spectrum. Similar to the three approved CDK4/6 inhibitors, CS3002 is highly selective for and potent against CDK 4 and 6, a feature that is expected to overcome the toxicity issues of pan-CDK inhibitors. Cell-based assays confirmed the biological activities of CS3002 by showing anti-proliferative effect, significant Rb phosphorylation inhibition, and G1 cell cycle arrest in a set of Rb-positive cancer lines. Furthermore, CS3002 showed excellent in vivo activity as a single agent, and in combinations with either endocrine therapy (fulvestrant) or PD-1 blockade (CS1003) in a set of tumor models, together with desirable ADME/PK and safety profile. CS3002 was further tested against 196 kinases in a Carna panel. In addition to CDK4 and CDK6, FLT3 and TRKA were also potently inhibited with IC50 values & lt;50nM. To this end, CS3002 demonstrated high activity in cell lines harboring NTRK1 fusion that were otherwise insensitive to CDK4/6 inhibitors. Across a panel of 19 AML cell lines, CS3002 demonstrated a similar sensitivity profile to gilteritinib (an approved FLT-3 inhibitor), but overall higher sensitivity compared to palbociclib. Interestingly, when MCF-7 breast cancer cell line was treated continuously with CS3002 in vitro, the emergence of drug-resistance was much delayed compared to treatment with palbociclib or abemaciclib. Given the encouraging preclinical properties as well as the unique potential in allowing indication expansion and delaying drug resistance to CDK4/6 inhibition, CS3002 is selected for clinical exploration in a Phase 1 study for advanced solid tumors (NCT04162301). Citation Format: Juan Zhang, Liang Tang, Zhenhu Li, Liang Lu, Yuanwu Bao, Zhaoxiang Ren, Jingshu Ma, Yaling Huang, Zhaobing Xu, Yuanfeng Xia, Charles Z. Ding, Lihong Hu, Shuhui Chen, Archie N. Xie, Xinzhong Jon Wang. CS3002, a novel CDK4/6 inhibitor with unique kinase inhibition spectrum which may expand indications beyond breast cancer and delay acquired drug resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4844.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-4844
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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