The VEGF pathway has emerged as an important target for cancer therapy by blocking the development of malignant neovasculature, thus to reduce oxygen availability to the tumor and decrease its growth. Anti-VEGF agents have been approved for several malignancies, such as GBM, NSCLC, mBC, CRC, OC, etc with satisfactory performance to extracranial lesions, but not in intracranial lesions. Insufficient penetration across BBB is one of factors limiting intracranial anti-tumor activity for those anti-VEGF agents, due to either large molecule weight or being substrate of BBB efflux transporters. The incidence of BM is increasing, and surgery/radiotherapy are the most common options for the management of BM. Patients with BM have a very poor prognosis and short survival. To address the role of anti-angiogenesis in the treatment of BM, a BBB penetrable, selective and potent VEGFR2 inhibitor WSD1227 is discovered with IC50 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. In-vitro MDCKII transfected cell assays demonstrated WSD1227 is not a substrate of P-gp or BCRP, two main efflux transporters on human BBB. Preclinical CNS PK studies confirmed brain penetration of WSD1227 with Kp,uu,brain close to unity, thus not exacerbating VEGF related systemic toxicities. WSD1227 possessed superior PK profile with sufficient free PK exposure to achieve target engagement in mice. Treatment of tumor bearing mice in GBM, NSCLC, CRC and OC xenograft models with WSD1227 resulted in significant tumor growth inhibition. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. 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.