Design and synthesis of novel small-molecule inhibitors of the hypoxia inducible factor pathway.
Hypoxia, a reduction in partial oxygen pressure, is a salient property of solid tumors. Hypoxia drives malignant progression and metastasis in tumors and participates in tumor resistance to radio- and chemotherapies. Hypoxia activates the hypoxia-inducible factor (HIF) family of transcription factors, which induce target genes that regulate adaptive biological processes such as anaerobic metabolism, cell motility, and angiogenesis. Clinical evidence has demonstrated that expression of HIF-1 is strongly associated with poor patient prognosis and activation of HIF-1 contributes to malignant behavior and therapeutic resistance. Consequently, HIF-1 has become an important therapeutic target for inhibition by small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 signaling pathway. Many of these compounds exhibit inhibitory activity in the nanomolar range. Separate mechanistic studies indicate that these inhibitors do not alter HIF-1 levels but interfere with the ability of HIF-1α/HIF-1β to interact with cofactors p300/CBP to form an active transcriptional complex.
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30302-4098, United States.
Suazette Reid
SR
Mooring
Hui
H
Jin
Narra S
NS
Devi
Adnan A
AA
Jabbar
Stefan
S
Kaluz
Yuan
Y
Liu
Erwin G
EG
Van Meir
Binghe
B
Wang
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors / Q000378:metabolism; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D000970:Antineoplastic Agents; D001572:Benzofurans; D001578:Benzopyrans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011725:Pyridines; D011804:Quinolines; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D050882:CREB-Binding Protein; D050880:p300-CBP Transcription Factors