Abstract 3096: Development of pyrrolopyrimidine-based ACK1 inhibitors for cancer therapeutics

Abstract

Abstract Activated CDC42-associated tyrosine kinase 1 (ACK1) is an enzyme encoded by the TNK2 gene. Studies have shown ACK1 phosphorylates proteins in oncogenic pathways active in lung, leukemia, ovarian, breast, and prostate cancers. Some of these phosphorylated proteins include tyrosine-kinase B (AKT), androgen receptor (AR), tumor suppressor WWdomain oxidoreductase (WWOX), proto-oncogene tyrosine-protein kinase (FYN), and growth factor receptor bound protein 2 (Grb2). ACK1 plays a pivotal role in leukemia, breast, and prostate cancer making it an attractive anticancer drug target. The development of novel ACK1 inhibitors using a pyrrolopyrimidine scaffold is described using molecular modeling and structure-activity relationships (SAR) studies. The synthesis of a focused library using a fragment-based design strategy will be highlighted as well as progress to optimize these compounds for potency, selectivity, and cell permeability. To gain structural insights for the development of novel, potent and selective ACK1 inhibitors, we have obtained X-ray structures of our compounds bound to human ACK1. We will describe the use of molecular docking to predict the binding mode of our compounds using both reported and our new ACK1 co-crystal structures. The key residues in the ATP binding pocket of ACK1 that are exploited for inhibitor design and kinase selectivity and synthetic routes to promising compounds will be discussed. We will present the KDs of the most potent compounds derived using a differential scanning fluorimetry (DSF) thermal shift assay and cellular activities in UKE1 leukemia and MB-231 breast cancer cell lines. We will present preliminary assessment of drug-like properties, used to optimize the inhibitor class for selection of a candidate for mouse studies. Overall, our work will highlight identification/optimization of novel ACK1 inhibitors via a fragment-based approach using pyrrolopyrimidine scaffolds and their potential use as anticancer agents. We will present the synthesis, SAR analysis, and the binding mode of these inhibitors. Citation Format: Angelie Matar, Yuliya Marusyk, Sujeewa Ranatunga, Tegan Rowsell, Narmin Amin, Hannah Walker, Timothy Tran, Kathy Yang, Derek Duckett, Gary Reuther, Harshani Lawrence, Nicholas Lawrence. Development of pyrrolopyrimidine-based ACK1 inhibitors for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3096.