7UAD

Crystal structure of human PTPN2 with inhibitor ABBV-CLS-484

7UAD の概要

• エントリーDOI: 10.2210/pdb7uad/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 2, 5-{(7R)-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1lambda~6~,2,5-thiadiazolidine-1,1,3-trione (3 entities in total)
• 機能のキーワード: phosphatase, inhibitor, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38351.45

構造登録者

Longenecker, K.L.,Qiu, W.,Sun, Q.,Frost, J.M. (登録日: 2022-03-12, 公開日: 2023-07-26, 最終更新日: 2023-11-08)

主引用文献

Baumgartner, C.K.,Ebrahimi-Nik, H.,Iracheta-Vellve, A.,Hamel, K.M.,Olander, K.E.,Davis, T.G.R.,McGuire, K.A.,Halvorsen, G.T.,Avila, O.I.,Patel, C.H.,Kim, S.Y.,Kammula, A.V.,Muscato, A.J.,Halliwill, K.,Geda, P.,Klinge, K.L.,Xiong, Z.,Duggan, R.,Mu, L.,Yeary, M.D.,Patti, J.C.,Balon, T.M.,Mathew, R.,Backus, C.,Kennedy, D.E.,Chen, A.,Longenecker, K.,Klahn, J.T.,Hrusch, C.L.,Krishnan, N.,Hutchins, C.W.,Dunning, J.P.,Bulic, M.,Tiwari, P.,Colvin, K.J.,Chuong, C.L.,Kohnle, I.C.,Rees, M.G.,Boghossian, A.,Ronan, M.,Roth, J.A.,Wu, M.J.,Suermondt, J.S.M.T.,Knudsen, N.H.,Cheruiyot, C.K.,Sen, D.R.,Griffin, G.K.,Golub, T.R.,El-Bardeesy, N.,Decker, J.H.,Yang, Y.,Guffroy, M.,Fossey, S.,Trusk, P.,Sun, I.M.,Liu, Y.,Qiu, W.,Sun, Q.,Paddock, M.N.,Farney, E.P.,Matulenko, M.A.,Beauregard, C.,Frost, J.M.,Yates, K.B.,Kym, P.R.,Manguso, R.T.
The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.
Nature, 622:850-862, 2023

PubMed Abstract: Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. 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 immunity. 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.

PubMed: 37794185
DOI: 10.1038/s41586-023-06575-7

実験手法

X-RAY DIFFRACTION (2.044 Å)