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Abstract 2203: WSD1227: A BBB penetrable VEGFR small molecule for the treatment of primary and metastatic brain tumors

Anti-angiogenesis has been proved to be a good strategy for cancer treatment (such as in GBM, NSCLC, mBC, CRC, OC, etc.) with satisfactory performance to extracranial lesions, but not in intracranial lesions. Insufficient penetration across BBB could be one of factors limiting intracranial activity for those approved anti-VEGF agents. There is a need to develop a BBB penetrable VEGFR inhibitor to clinic to assess the efficacy and safety. Here we report that WSD1227, a novel, selective VEGFR inhibitor, displays potent activity, excellent CNS penetration and preclinical safety and efficacy. The IC50 of WSD1227 against VEGFR1/2/3 at 0.69/0.35/0.41nM versus against other targets such as PDGFRα IC50 22.9nM, PDGFRβ IC50 19.4nM, cKit IC50 383nM, FLT3 IC50 555 nM and CSF1R IC50 1062nM. WSD1227 treatment resulted in significant anti-tumor activity in VEGF related extracranial and intracranial mice models, with superior efficacy than bevacizumab. There is no increased risk of CNS hemorrhage in intracranial tumor bearing mice treated with WSD1227. In addition, WSD1227 is predicted to be CNS penetrable with decent PK in human. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic to investigate anti-angiogenetic therapies for management of patients with primary or metastatic brain tumors. Citation Format: Jinqiang Zhang, Wei Zhong, Zhihua Mu, Claire Sun. WSD1227: A BBB penetrable VEGFR small molecule for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2203.