Abstract 4793: WSD1227: A novel, oral bioavailable, brain penetrable and reversible VEGFR inhibitor for the treatment of primary and metastatic brain tumors

Abstract

Abstract Occurrence of brain metastases (BM) has been reported in ~10% cancer patients as a later manifestation of the disease with incidence depending on the type of primary tumors1: about 20~40% in NSCLC and BC2,3 and <5% in CRC4,5 and ovarian cancer (OC)6. The incidence of BM is increasing in part due to the earlier diagnosis by using brain imaging techniques and the improved survival offered by systemic therapies. Patients with BM have a very poor prognosis and the overall survival is only several months after diagnosis. Surgery and radiotherapy either as single treatment or in combination are the most common options for the management of BM since many anticancer drugs cannot cross the blood-brain barrier (BBB). VEGFR2, upregulated in many cancers7,8, plays an important role in tumor angiogenesis. Anti-angiogenesis has been proved to be a good strategy to shrink tumor in many cancer treatments, such as bevacizumab in GBM, NSCLC, mBC, cediranib in OC, etc. However, those clinical validated anti-VEGF agents cannot cross BBB effectively due to either large molecule weight or being substrate of BBB efflux transporters. Herein, using our advanced medicinal chemistry with deep knowledge in CNS area, a BBB penetrable, selective and potent VEGFR2 inhibitor WSD1227 is discovered with biochemical 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 good brain penetration of WSD1227 with Kp,uu,brain close to unity. WSD1227 possessed superior PK profile with sufficient free PK exposure to achieve target engagement in mice. Treatment of mice bearing SW620, a CRC xenograft in both subcutaneous (SC) and intracranial models with WSD1227 after oral dosing resulted in significant tumor growth inhibition (TGI). Similar TGI was observed in SKOV-3 bearing mice, an OC xenograft in both SC and intracranial models. No toxicity was observed in the animals during the treatment. Moreover, predicted human PK properties are very promising to offer sufficient target engagement at a pretty low dose in clinic. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic for the treatment of patients with BM whose primary tumors have already been controlled well by systemic therapies. Citation Format: Jinqiang Zhang, Wei Zhong, Zhihua Mu, claire sun. WSD1227: A novel, oral bioavailable, brain penetrable and reversible VEGFR inhibitor for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4793.