Abstract #2053: Novel oral SHP-1 inhibitors exhibit pre-clinical anti-melanoma activities via activating immune cells

Abstract

Protein tyrosine phosphatases, like protein kinases that have been targeted successfully with inhibitors for clinical cancer treatment, are promising cancer therapeutic targets. However, proof of concept remains to be established and research progression has been hampered by the limited number of identified phosphatase inhibitors with pre-clinical anti-cancer activity. Phosphatase SHP-1 is a key negative regulator in immune cells and an attractive target to augment anti-cancer immunity. Indeed, SHP-1 inhibitory agent SSG, which was effective at low \#956;M levels, induced IFN\#947;+ immune cells for pre-clinical anti-tumor action and is in early phases of clinical trials. To develop novel and more potent SHP-1-targeted anti-cancer agents, SHP-1 inhibitory lead compound L5 was identified from a library of 34,000 drug-like small chemicals and evaluated for its pre-clinical activities in inhibiting intracellular SHP-1, inducing IFN\#947;+ immune cells and in anti-melanoma action. L5 inhibited intracellular SHP-1 at 10 ng/ml with little effects on phosphatases SHP-2 and CD45 in Jurkat T cells. L5 induced mouse spleno-IFN\#947;+ cells in vitro, ~58-fold more effective than SSG. In vivo spleno-SHP-1 inhibition and -IFN\#947;+ cell induction were evident in L5-treated mice. Significantly, L5 inhibited (83%, p <0.002) the growth of SSG-refractory B16 melanoma tumors in mice at a tolerated oral dose (~3 mg/kg body weight) in a T cell-dependent manner whereas it failed to inhibit B16 cell growth in culture. L5 was also highly effective in inducing IFN\#947;+ cells (20-fold) in human peripheral blood in vitro in comparison to SSG (3-fold). Several analogs of L5 were identified and exhibited improved activities (~2-4 x) in inducing mouse spleno-IFN\#947;+ cells in vitro and in anti-melanoma action in mice as tolerated oral agents. The lead compounds also exhibited pre-clinical activities against colon cancer tumors. These results designate L5 and analogs as novel SHP-1 inhibitors with pre-clinical anti-cancer activities via an immune mechanism, demonstrate the potential of refining the lead compounds to develop oral therapeutics for enhancing anti-cancer immunity, and provide further supporting evidence for targeting SHP-1 in cancer treatment.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2053.