5UFP

Crystal structure of PT2399 bound to HIF2a-B*:ARNT-B* complex

Replaces:  5T0T

Summary for 5UFP

• Entry DOI: 10.2210/pdb5ufp/pdb
• Descriptor: Endothelial PAS domain-containing protein 1, Aryl hydrocarbon receptor nuclear translocator, 3-({(1S)-7-[(difluoromethyl)sulfonyl]-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl}oxy)-5-fluorobenzonitrile, ... (4 entities in total)
• Functional Keywords: hif2 inhibitor hif2 ligand pas-b hypoxia inducible factor 2 epas1, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q99814 P27540
• Total number of polymer chains: 2
• Total formula weight: 27467.92

Authors

Du, X. (deposition date: 2017-01-05, release date: 2017-01-25, Last modification date: 2024-03-06)

Primary citation

Cho, H.,Du, X.,Rizzi, J.P.,Liberzon, E.,Chakraborty, A.A.,Gao, W.,Carvo, I.,Signoretti, S.,Bruick, R.K.,Josey, J.A.,Wallace, E.M.,Kaelin, W.G.
On-target efficacy of a HIF-2 alpha antagonist in preclinical kidney cancer models.
Nature, 539:107-111, 2016

PubMed Abstract: Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2α transcription factor (also known as EPAS1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.

PubMed: 27595393
DOI: 10.1038/nature19795

Experimental method

X-RAY DIFFRACTION (1.9 Å)