Abstract 5869: TT-00420, a dual mechanism kinase inhibitor targeting both mitosis and tumor microenvironment, is highly active against TNBC both in vitro and in vivo

Abstract

Abstract The hallmarks of cancer comprise dysregulated cell cycle and mitosis, active angiogenesis, tumor-promoting inflammation, and immune escape as well as other features. Therapeutic targeting one of the hallmarks has shown promising but short-lived efficacy in cancer therapy. Therefore, combination of two or more mechanisms holds great promise of next generation oncology drug development. Aurora kinase A and B are often over expressed in many malignancies and associated with poor prognosis. Several anti-angiogenesis agents have been approved alone or in combination with other oncology drugs. In addition to its role for tumor growth, recent studies illustrate that angiogenesis also plays critical roles in the complexity and dynamic regulation of tumor microenvironment (TME). With the rapid advancement of immune-oncology, several attractive targets involved in tumor-promoting inflammation and immune escape have emerged. We have focused our efforts on the discovery and development of small molecule kinase inhibitors with novel mechanisms to treat cancer. Kinase profiling showed that TT-00420, one of our leading compounds, inhibited Aurora A/B, RTKs involved in angiogenesis, and a few other targets directly involved in tumor-assocated inflammation and immune escape with low nano molar activities. In a screening of human breast cancer cell lines, TT-00420 was highly efficacious against triple negative breast cancer (TNBC) cells while leaving ER+ cells intact, which is completely complimentary to the activity of CDK4/6 inhibitors. This anti-TNBC activity was confirmed in a patient derived xenograft (PDX) TNBC model in vivo, in which TT-00420 was highly active both as first-line and second-line treatment. TT-00420 demonstrated good oral bioavailability and pharmacokinetic properties in mice, rats and dogs. 2-week repeated dose-range finding studies revealed mechanism-related but manageable toxicities of TT-00420 in the 3 species mentioned above. Its dual mechanism involving anti-mitosis and TME modulation will be discussed in this presentation. TT-00420 is now under active development for IND filings both in the US and China. Citation Format: Peng Peng, Xiaoju Yang, Xiaoyan Qiang, Lin Li, Shumao Ni, Xiaofen Sun, Di Wu, Frank Wu. TT-00420, a dual mechanism kinase inhibitor targeting both mitosis and tumor microenvironment, is highly active against TNBC both in vitro and in vivo [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 5869.