Abstract Background: Emerging evidence highlights sympathetic innervation is a key component of the tumor microenvironment, and that denervation effectively suppresses tumor growth, revealing new therapeutic opportunities (Vera Thiel, Nature 2025). α2A-adrenoceptor (α2AAR) agonists like clonidine are potent regulators of sympathetic activity, and have demonstrated antitumor efficacy (Jingjing Zhu, Nature 2023), yet their application in oncology can be severely limited by the central nervous system (CNS)-mediated adverse effects, including sedation and hypothermia. To overcome this challenge, we developed CC10230, a novel peripherally restricted α2AAR agonist designed to provide sustained antitumor therapy without dose-limiting CNS toxicity. Method: A focused compound library was generated through rational design and screened based on in vitro α2AAR potency, P-gp efflux ratio, and oral bioavailability. Peripheral restriction of the lead compound was confirmed using in vivo distribution pharmacokinetic. Anti-tumor activity was assessed in the MC38 subcutaneous tumor model in mice, and anti-allodynic efficacy was evaluated in the NCTC-2572 cell-induced bone cancer pain model in mice. All clinical observations, including behavior and safety monitoring, were conducted in accordance with CRO's standard operating procedure (SOP). Result: CC10230 was selected as a lead compound based on its high α2AAR activity (EC50= 7.5 nM, Ki = 58.1 nM), strong P-gp substrate properties (efflux ratio = 51.0), and a favorable oral bioavailability (44.6%). Pharmacokinetic studies confirmed minimal CNS penetration (Kp,uu,brain 0.03), markedly lower than that of clonidine, supporting strong peripheral restriction. In the MC38 model, CC10230 (5 mg/kg, b.i.d., p.o.) significantly suppressed tumor growth, achieving a TGI of 62.3% at Day 17. Clonidine (5 mg/kg, b.i.d., p.o.) as a positive control also achieved significant TGI but was poorly tolerated, causing pronounced somnolence, hypothermia, and 18.1% body weight loss. In contrast, CC10230 showed no tolerability issues. Additionally, CC10230 exhibited robust efficacy in cancer pain model, confirming its dual therapeutic benefits. Conclusion: These findings establish peripheral α2AAR activation as a promising two-pronged translational strategy for integrated oncology care, simultaneously inhibiting tumor progression and alleviating cancer-related pain while circumventing CNS-mediated side effects. The favorable safety profile of CC10230 supports its potential for sustained antitumor therapy without the tolerability limitations of conventional α2AAR agonists. Citation Format: Zhiqiang Cheng, Yang Xu, Larry Zhu. Targeting peripheral α2A-adrenoceptors as a dual-benefit approach for integrated cancer therapy and supportive care abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5121.
Cheng et al. (Fri,) studied this question.