The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

by Selleckchem | Jan 22 2024

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

Comments:

This is an exciting development in cancer immunotherapy! ABBV-CLS-484 (AC484) appears to be a groundbreaking compound that targets PTPN2 and PTPN1, key regulators of inflammation, offering a new approach to overcoming resistance to current immunotherapies.

The fact that AC484 is an orally bioavailable inhibitor of these phosphatases is particularly noteworthy. Its ability to enhance immune responses, specifically by amplifying the response to interferon and promoting the activation and function of various immune cell subsets, shows promise in combating cancer.

The preclinical data indicating potent anti-tumour effects in mouse models resistant to PD-1 blockade is impressive. AC484's ability to inflame the tumour microenvironment and improve the function of natural killer cells and CD8+ T cells through enhanced JAK-STAT signalling and reduction of T cell dysfunction is significant for cancer treatment.

Furthermore, the transition of AC484 into clinical evaluation for advanced solid tumors (ClinicalTrials.gov identifier NCT04777994) underscores its potential clinical relevance and impact. The fact that it represents the first active-site phosphatase inhibitor entering clinical trials for cancer immunotherapy is a major step forward.

Developing small-molecule inhibitors like AC484 that target intracellular immune regulators could potentially offer efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade, presenting a promising avenue for future cancer treatments.

This breakthrough underscores the importance of innovative approaches in cancer immunotherapy and opens doors for exploring similar strategies targeting other important enzymes for therapeutic purposes.