Protein Homeostatic Modulators (PHMs™)
Protein Homeostatic Modulators are proprietary small ‘molecular glue’ cereblon (CRBN) binders that have clinically relevant substrate degradation profiles offering vast therapeutic opportunities across oncology, inflammation and other diseases. These binders play a key function in the protein degradation process through ubiquitination. PHMs are capable of restoring protein homeostasis through degrading select targets, many of which were previously considered ‘undruggable’. BioTheryx’s family of PHMs has over 20 structural scaffolds which have a broad range of molecular orientations when bound to CRBN offering the company a unique position in protein degradation.
Proteolysis targeting chimeras, more commonly known as PROTACs, are molecules that have two operative ends – one a ligand that binds to an E3 ligase, and the other a ligand that binds to the protein targeted for degradation. These two ends are connected by a chemical chain linker. This approach is appealing in the sense that known therapeutic targets of interest can be “tagged” for ubitiquination via the ubiquitin proteasome system by conjugating them to a cereblon(CRBN)-binding molecule.BioTheryX’s PHM-based PROTACs hold several advantages over companies pursuing proteolysis targeting chimeras that bind to the E3 ligase CRBN. The large diversity of our proprietary PHM binders offers a superior level of structural control in the creation of PROTACs that degrade high-value clinical targets. As even small changes in the orientation of CRBN-binding can lead to profound differences in the activity of compounds, our approach has unique probability of success and robust commercial freedom to operate. Our lead PHM-PROTACs have shown excellent pre-clinical efficacy to date.
Our lead clinical candidate, BTX-A51, is an oral small molecule, multi-kinase inhibitor designed to block a specific leukemic stem cell target (CK1α) as well as super enhancer targets (CDK7/CDK9) preventing transcription of key oncogenic genes. This therapeutic mechanism entails activation of p53 (an important tumor suppressor) and its sustained stabilization by super-enhancer shutdown of Mdm2 (a protein degrader of p53), in combination with transcriptional shutdown of leukemia oncogenes, such as Myc and Mcl1.Blocking CKIα, CDK7, and CDK9 augments and synergistically stabilizes p53. This deprives leukemia cells of survival and proliferation, inducing apoptosis. Pre-clinical results published in the prestigious, peer-reviewed Cell journal demonstrated BTX-A51’s remarkable efficacy in animals.
- Inhibition of Casein Kinase 1 Alpha in Acute Myeloid Leukemia - N Engl J Med, November 2018
- Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models – Cell, August 2018
- Targeting the Transcriptional Addiction of Leukemia Stem Cells by a New Class of Protein Kinase Inhibitors – ASH, December 2017, Oral Presentation
- Protein Homeostatic Modulators, a Novel Class of Cereblon-Targeting Small Molecules as Potential Clinical Candidates in Multiple Myeloma – ASH, December 2017, Poster Presentation
- Novel Small Molecule Inhibitors Co-Targeting CK1a and P-Tefb Disrupt Super-Enhances and Eradicate Acute Myeloid Leukemia in a Mouse Model – EHA, June 2017, Late Breaking Abstract