Abstract 3760: HH2710, a highly potent and selective erk1/2 inhibitor for the treatment of mapk mutant tumors

Abstract

Abstract The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, is the most frequently mutated signal pathway in cancer, which makes the components of this pathway attractive targets for anticancer drug development. The MAPK pathway is aberrantly activated in more than 30% of human cancers through a high frequency of genetic alteration. BRAF mutation has been identified in colorectal (10%), thyroid (∼50%) and melanoma (60%) tumors, whereas RAS is mutated in melanoma (20%), colorectal (50%) and pancreatic (90%) tumors. Thus far, inhibitors targeting the upstream BRAF and MEK have been the focus of past decades and achieved great clinical successes, but remained being challenged by the acquired resistance due to genetic alterations in RAS, BRAF or MEK. Therefore, targeting the downstream ERK is believed to exhibit potential advantages in both effectively shutting down MAPK signaling cascade and overcoming the resistance to upstream targets. Toward that end, we developed a novel ERK1/2 inhibitor, HH2710, which is a highly potent and selective inhibitor of ERK1 and ERK2 with IC50 of 4.5, 4.9 nM, respectively. HH2710 significantly inhibited the downstream RSK phosphorylation in a dose-dependent manner in both BRAF and RAS mutant cancer cell lines. HH2710 strongly inhibited the proliferation of most BRAF mutated cancer cell and a proportion of RAS mutated cells, with IC50s ranging from 0.2 to 4.5 μM. In tumor xenograft models, HH2710 showed significant antitumor activity at the doses of 15, 30, and 60 mg/kg (twice per day, given orally) with the relative tumor volume at the endpoint (T/C value) of 51.0%, 18.1%, and 11.7% respectively, exhibiting improved efficacy over the front runner molecule in clinical development. Summary of pharmacokinetic parameters are listed in Table 1. The full in vitro and in vivo preclinical characterizations of HH2710 will be presented. Table 1, Pharmacokinetic parameters of HH2710 in mouse, SD rats and Beagle dogs ParametersnCmax*nAUC0-t*t1/2TmaxFµg/mLµg•h/mLhh(%)Mouse, PO0.5031.811.12.065Rat, PO0.2691.773.02.068Dog, PO0.3381.642.01.573*nCmax: Cmax/dose; nAUC0-t : AUC0-t/dose Citation Format: Lei Li, Min Huang, Leping Li, Yi Chen, Shuai Tang, Yi Su, Ruiping Dong, Jian Ding, Meiyu Geng. HH2710, a highly potent and selective erk1/2 inhibitor for the treatment of mapk mutant tumors [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 3760.