Inhibition of HIF-2α heterodimerization with HIF1β (ARNT)
Provided is a method of inhibiting heterodimerization of HIF-2α to HIF1β (ARNT) comprising binding certain small molecules to the HIF-2α PAS-B domain cavity but not to HIF1α and inhibiting HIF-2α heterodimerization to HIF1β (ARNT) but not inhibiting HIF1α heterodimerization to HIF1β (ARNT). Those certain small molecules are also referenced synonymously as HIF2-HDI and HIF2α heterodimerization inhibitors and also simply as certain small molecules.
1. A bound HIF-2α PAS-B domain comprising a small molecule bound to at least four or more amino acids selected from the group consisting of PHE-244, SER-246, HIS-248, MET-252, PHE-254, ALA-277, PHE-280, TYR-281, MET-289, SER-292, HIS-293, LEU-296, VAL-302, VAL-303, SER-304, TYR-307, MET-309, LEU-319, THR-321, GLN-322, GLY-323, ILE-337, CYS-339, and ASN-341 of said HIF-2α PAS-B domain, wherein said small molecule is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from NH and NH(CH 2 );
R 1 is NO 2 ;
R 2 is independently selected from NO 2 , halo, and alkyl optionally substituted with at least one halo; and
p is 1, 2, 3, 4, or 5.
2. The bound HIF-2α PAS-B domain of claim 1 , wherein said small molecule is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3. The bound HIF-2α PAS-B domain of claim 1 , wherein R 2 is independently selected from halo, methyl, and methyl substituted with at least one fluoro.
4. The bound HIF-2α PAS-B domain of claim 1 , wherein p is 1 or 2.
5. The method of claim 1 , wherein said compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.