Structure/Function of Protein Tyrosine Phosphatases

Purdue University, West Lafayette IN

Investigators

Linked publications & trials

Abstract

Abstract Aberrant cell signaling stemming from altered protein tyrosine phosphorylation is a major contributing factor to human diseases including cancer. Consequently, anomalous cellular events driven by defective protein tyrosine phosphorylation afford tremendous therapeutic opportunities. Success for such targeted approach is evident by the abundance of protein tyrosine kinase-based therapeutics. Given the reversible nature of protein tyrosine phosphorylation, there is enormous potential to target protein tyrosine phosphatases (PTPs) for disease intervention. However, despite increasing interest in PTPs, they still remain largely an underexploited target class. Among major factors that contribute to the difficulty of PTP-based drug discovery are the lack of understanding of PTPs in disease biology (i.e. insufficient target validation) and challenges in developing PTP- specific small molecule probes for functional interrogation and therapeutic development. The broad, long-term objectives of this program are to define the structure and function of PTPs and to utilize this knowledge to advance drug discovery by targeting them. With the support of this grant in the last five years, we elucidated the oncogenic mechanism by which the PRL2 phosphatase promotes tumorigenesis and established PRL2 as an exciting target for PTEN augmentation therapy. In the next five years, we will focus on SHP1, encoded by Ptpn6, to develop novel cancer immunotherapeutic agents. Although current immunotherapies achieve durable efficacy in some patients, responses for many tumors remain very low. Thus, there is an urgent need for new approaches. To this end, SHP1 is primarily expressed in hematopoietic cells, negatively regulates immune functions and is an intracellular mediator of inhibitory signals transmitted by immune checkpoint receptors. Importantly, SHP1 deletion improves anti-tumor immunity in mice, implicating SHP1 as a promising target for cancer immunotherapy. We hypothesize that potent and selective SHP inhibitors serve as novel immunotherapeutic agents. Unfortunately, no small molecule SHP1 inhibitor exists to demonstrate the translatability of this target. The goal of this proposal is to develop SHP1 inhibitors with the requisite potency, selectivity and drug-like properties to interrogate the therapeutic potential of SHP1 as a cancer immunotherapy target. We have discovered a novel orally efficacious allosteric covalent SHP1 inhibitor (M029), which targets a cryptic Cys residue in SHP1 and selectively inhibits SHP1 phosphatase activity over a large panel of PTPs. Moreover, M029 enhances T-cell activation and exhibits anti-tumor activity in vivo. We will use a focused medicinal chemistry approach guided by computational modeling and co-crystal structures to develop optimized SHP1 inhibitors that can be evaluated either stand-alone and/or in combination with immune checkpoint inhibitors as novel cancer immunotherapy using syngeneic immunocompetent mouse models. These studies serve to pharmacologically validate SHP1 as a new cancer immunotherapy target and provide prototype drugs that can be further optimized for eventual clinical translation.