Incubating Progress: HIF2/Kidney Cancer

The Foundations

Dr. Richard Bruick
Dr. Richard Bruick


UT Southwestern biochemist Dr. Steven McKnight and molecular geneticist Dr. David Russell lead research discovering and describing the protein encoded by the EPAS-1 gene, also known as HIF-2α. Additional research at UT Southwestern sheds more light on the workings of the HIF family and related molecules, especially HIF-2α.


Over the course of a decade, the laboratories of Drs. Richard Bruick and Kevin Gardner tease apart the structure of HIF-2. Biochemical analysis reveals how HIF-2α docks with another protein to assemble into a functional HIF-2 complex, and how mutations that disrupt this binding halt HIF-2 activity. Finding drug-like chemicals that can likewise disrupt HIF binding holds the promise of impairing various downstream cancer-promoting targets, such as the VEGF receptor.


The Bruick-Gardner research reveals a cavity within the HIF-2α protein that is a potential “sweet spot” where disrupters may bind and shut down HIF-2 activity.

The Translation

HIF-2 molecule called the HIF-2α PAS-B
Tucked in the cavity found in a part of the HIF-2 molecule called the HIF-2α PAS-B domain are two different small molecule disrupters of HIF-2 discovered by the UT Southwestern team. (Data from T.H. Scheuermann et al., Nat. Chem. Biol. 9[2013]: 271 and T.H. Scheuermann et al., J. Med. Chem. 58[2015]: 5930; image from Kevin Gardner)


After gleaning insights from earlier, more focused screens, scientists deploying the Cancer Center’s High-Throughput Screening Shared Resource systematically test more than 200,000 drug-like molecules, one at a time, to see which ones might interfere with HIF-2. The effort identifies a slate of successful compounds.


Medicinal chemists at Simmons Cancer Center study the HIF-2 disrupters, learning more about how they work and refining the most promising of these compounds to increase their potency and improve their safety profile


UT Southwestern scientists including Drs. Richard Bruick, Kevin Gardner, John MacMillan, and Uttam Tambar detail how chemicals bind with the “sweet spot” cavity to disrupt HIF-2 function.  The findings indicate that small molecules can feasibly regulate HIF-2α, a type of molecule previously considered “undruggable.”

Research shows that the newly discovered and refined compounds can block the assembly of the HIF-2 complex and disrupt its function in living cells originating from actual human tumors—rendering HIF-2 unable to turn on other cancer-related genes.

Human cells respond to low oxygen levels (hypoxia) using the hypoxia inducible factor, or HIF, complex (near center of diagram) assembled from two proteins: HIFα and ARNT. When oxygen levels fall, the HIFα subunit can accumulate in the cell nucleus, where it binds to ARNT, forming HIF complexes. These complexes control transcription (depicted at right) of more than 100 genes affecting the cell’s ability to adapt and respond to hypoxia. Small molecules developed at UT Southwestern can bind to the HIF-2α subunit to disrupt its activity in cancer cells (also depicted at right). (Illustration by Gardner/Bruick)

The Impact


The most promising compounds are licensed to Peloton Therapeutics, a biotech firm co-founded by Dr. McKnight and based in new  state-of-the-art facilities on UT Southwestern’s BioCenter campus.


The first HIF-2 inhibitor in clinical development, an oral drug known as PT2385, enters a phase I clinical trial for safety and dosing in patients with advanced or metastatic renal clear cell carcinoma. Dr. Kevin Courtney heads the trial at UT Southwestern, one of several sites across the U.S. testing the drug.

The Future

Dr. Kevin Gardner
Dr. Kevin Gardner

A mouse model of human renal clear cell carcinomas, developed and validated by UT Southwestern kidney cancer specialist Dr. James Brugarolas and colleagues, may provide insights into which patients are most likely to benefit from treatment with HIF-2 inhibitors. HIF-2 also appears significant in other types of cancer, including deadly brain cancers called glioblastomas and non-small cell lung cancer, the most common type of lung malignancy.






Go to Incubating Progress: Lung Cancer >