osunprotafib (ABBV-CLS-484)

It enhanced lymphocyte infiltration into tumors and modulated IFN-γ signaling pathways. These findings indicate that compound K-38 is a potent small molecule inhibitor of PTPN2, laying the groundwork for the future development of PTPN2-targeted therapeutics.

In B16-OVA syngeneic models, WS35 monotherapy and its combination with an anti-PD-1 antibody achieved robust tumor growth suppression, outperforming AC484, with no observable systemic toxicity. Collectively, WS35 represents a preclinical candidate with validated efficacy and safety for developing novel antimelanoma therapeutics.

Interestingly, TFRC is directly regulated by the transcription factor hypoxia-inducible factor 1 alpha (HIF1A) in its promoter. Notably, an orally bioavailable potent PTPN2/N1 active-site inhibitor ABBV-CLS-484 (AC484) demonstrates significant therapeutic potential against ALK+ ALCL by disturbing mitochondrial renewal and blocking TFRC-mediated PINK1-PRKN-dependent mitophagy to exert anti-tumor activities, providing critical insights into the selection of targeted treatment strategies for ALK+ ALCL patients and a strong rationale for advancing AC484 into clinical trials.

P1, N=248, Recruiting, AbbVie | Trial primary completion date: Aug 2025 --> Oct 2026

This review outlines the structural modification processes of PTPN2-targeted agents, focusing primarily on inhibitors and degraders. Finally, this review endeavors to provide a comprehensive perspective on the evolving field of PTPN2-targeted drug discovery for tumor immunotherapy, offering valuable insights for future drug development.

The small molecule ABBV-CLS-484 (AC-484) is an active site inhibitor of PTPN1 and PTPN2 currently in clinical trials for advanced solid tumors. We compared AC-484 and HODHBt and found similar effects on STAT5 and immune activation albeit with different mechanisms of action leading to varying effects on latency reversal. Our studies provide the first specific evidence that enhancing STAT phosphorylation via inhibition of PTPN1 and PTPN2 is an effective tool against HIV.

P=N/A, N=0, Available, Calico Life Sciences LLC

P1, N=248, Recruiting, Calico Life Sciences LLC | Trial completion date: Feb 2024 --> Oct 2026 | Trial primary completion date: Oct 2023 --> Aug 2025

The advent and clinical success of immune checkpoint inhibitors Ipilimumab, Nivolumab and Pembrolizumab has had a seismic impact on our drug discovery focus and rationale. In a recent publication, Baumgartner et al. demonstrate the pre-clinical efficacy of a first-in-class dual PTPN1/N2 active site inhibitor (ABBV-CLS-484/AC484) in cancer models.

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.

ABBV-CLS-484 is a PTP1B/PTPN2 inhibitor in clinical trials for solid tumors...Importantly, treatment with Compound-182 rendered otherwise resistant tumors sensitive to α-PD-1 therapy. Our findings establish the potential for small molecule inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer.

Preclinical data also indicated that PTPN2/1 inhibitors have improved efficacy when combined with PD-1-targeting agents (eg, pembrolizumab) or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in multiple tumor models. Evaluation of objective response rate (RECIST v1.1) is a primary objective in EXP phase and a secondary objective in ESC phase. Both studies are active, and as of 30 Nov 2022, 30 (ABBV-CLS-484) and 45 (ABBV-CLS-579) patients had been enrolled in ESC phase.