Design and Synthesis of Novel Small-Molecule Inhibitors of the Hypoxia Inducible Factor Pathway

Abstract

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 HIF-1α/HIF-1β/p300/CBP complex formation by interacting with p300 and CBP.

Structure–activity relationship of 2,2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, a novel small molecule hypoxia inducible factor-1 (HIF-1) pathway inhibitor and anti-cancer agent

“…19,21 In the current experimental set the IC 50 value of 6e (1.6 μM) was larger than the previous values; this variation might be related to the particular batch of cells used and the smaller number of repeats ( n = 6). Because this compound was used as an internal standard we used the latter value for comparison with the other compounds tested under the same conditions.…”

“…1), which showed strong inhibition of reporter activity under hypoxia. 19–21 Further testing of 6e revealed that it has potent anti-cancer properties in animal models for brain cancer (glioblastoma), eye cancer (uveal melanoma) and pancreatic cancer (manuscripts in preparation). However, the treatment necessitated delivery of 6e in a formulation, due to poor water solubility (<15 μg/mL; pH7.4), suggesting that further pharmacological optimization is necessary before this family of compounds can be translated to the patient.…”

Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor

“…In the present context, we define true positives as compounds with an average IC 50 value <650 nM. Five of 30 analogues fall in this category based on the cell-based reporter assay: 648, 306, 478, 378, and 280 nM activity (See Table 10, ref 17).…”

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

“…Those strategies were mostly aimed at modulation of HIF-1a expression level by compounds affecting its transcription/ translation, 7 compounds activating PHD proteins which promote HIF-1a degradation in a VHL dependent manner, 8 and compounds affecting HIF-1a/ ARNT/p300/CBP complex formation by binding to p300/CBP. 9 Additionally, an RNA antagonist, EZN-2968, composed of a third-generation oligonucleotide, locked nucleic acid technology that specifically binds and inhibits the expression of HIF-1a mRNA was developed and shown to inhibit tumor cell growth in glioblastoma and prostate cancer models. 10 A second HIF isoform, HIF-2a, was identified that is regulated in a manner similar to HIF-1a.…”