7TVA

Stat5a Core in complex with AK2292

Summary for 7TVA

• Entry DOI: 10.2210/pdb7tva/pdb
• Descriptor: Signal transducer and activator of transcription 5A, N-{5-[difluoro(phosphono)methyl]-1-benzothiophene-2-carbonyl}-3-methyl-L-valyl-L-prolyl-N-(5-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}pent-4-yn-1-yl)-N-methyl-N~3~-[4-(1,3-thiazol-2-yl)phenyl]-beta-alaninamide, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• Functional Keywords: stat5a, activator, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 134112.01

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2022-02-04, release date: 2023-02-15, Last modification date: 2024-04-03)

Primary citation

Kaneshige, A.,Bai, L.,Wang, M.,McEachern, D.,Meagher, J.L.,Xu, R.,Wang, Y.,Jiang, W.,Metwally, H.,Kirchhoff, P.D.,Zhao, L.,Jiang, H.,Wang, M.,Wen, B.,Sun, D.,Stuckey, J.A.,Wang, S.
A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo.
Nat.Chem.Biol., 19:703-711, 2023

PubMed Abstract: Signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target, but successful targeting of STAT5 has proved to be difficult. Here we report the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and more than 6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and the therapeutic potential of selective STAT5 protein depletion and inhibition but also a promising lead compound toward ultimate development of a STAT5-targeted therapy.

PubMed: 36732620
DOI: 10.1038/s41589-022-01248-4

Experimental method

X-RAY DIFFRACTION (2.835 Å)