indivdual blood cells viewed down a microscope, several form a crescent shape rather than the healthy round form.
Credit: Shutterstock
A microscope image of sickle cell red blood cells.
The targeted protein degrader BMS-986470 from Bristol Myers Squibb (BMS) boosts levels of fetal hemoglobin in cells, mice, and monkeys, the company reported this weekend at the American Society of Hematology (ASH) meeting. The dual Wiz and ZBTB7A degrader entered into a first Phase 1/2 sickle cell disease trial in July, 1 month ahead of a similar compound from Novartis.
“It’s a super exciting molecule and a fantastic exemplar of what we think is possible with targeted protein degraders,” Neil Bence, head of oncology discovery at BMS and who worked on the BMS-986470 program, tells C&EN.
Molecular glue-based degraders, small molecules that shunt proteins of interest to the cell’s garbage disposal system, have been making waves in oncology. The advancing sickle cell disease candidates showcase their potential in other diseases as well, Bence says.
Sickle cell disease affects around 8 million people worldwide. It is caused by mutations in theββ-globin protein that warp red blood cells and cause periodic pain crises and serious health complications. Last year, the US Food and Drug Administration approved Casgevy from Vertex Pharmaceuticals and CRISPR Therapeutics. It is a CRISPR-based medicine for sickle cell disease that partially silences BCL11A to boost the production of fetal hemoglobin, which is made with γ-globin. Blood cells typically stop making fetal hemoglobin after birth, but low levels of fetal hemoglobin can compensate for the loss of functional β-globin.
Casgevy is complex to administer and expensive, however, leaving a need for globally accessible treatment options.
Researchers at BMS think that molecular glue degraders could be up to the task. When researchers at BMS screened their degrader library for compounds that boosted γ-globin production, their top contenders were dual degraders of the Wiz and ZBTB7A transcription factors, the company reported at the ASH meeting.
Transcription factors are proteins that regulate gene expression to control critical cellular programs, including hemoglobin production. The transcription factors Wiz and ZBTB7A both contain G-loop degrons, the canonical binding interface for known glue degraders.
When the team treated human blood cells, mice, and monkeys with their lead drug candidate, BMS-986470, fetal hemoglobin levels rose markedly. “In preclinical models, it induces fetal hemoglobin to levels that are predicted to offer functional cure potential,” Bence says.
“The preclinical data are intriguing but do not guarantee that they translate to the in vivo setting,” cautions Stuart Orkin, a sickle cell expert at Boston Children’s Hospital whose work paved the way for Casgevy. “Bottom line: only time will tell.”
BMS isn’t the only firm trying to use degraders to tackle sickle cell disease. Novartis has a Wiz-targeting glue degrader, ITU512, that also induces γ-globin production and is also now in the clinic (Science 2024, DOI: 10.1126/science.adk6129).
Researchers from Mass General Brigham also reported at this year’s ASH meeting that a dual degrader of ZBTB7A and BCL11a appears to boost fetal hemoglobin levels. “We are in the very early, preclinical stages of research with this molecule,” says Jun Liu, the postdoc-physician who led this research.
The molecule, dubbed SH6, appears to act through a new binding motif on these transcription factor targets, according to a preprint published before peer review (bioRxiv 2024, DOI: 10.1101/2024.01.03.574032). More work is needed to determine how it degrades its targets, adds Liu.
With the degraders from BMS and Novartis now both in clinical trials, all eyes are on their safety and efficacy. Wiz is expressed by many cell types and has broad regulatory effects, raising the risks of unacceptable side effects. ZBTB7A also has complex biology, with key roles in blood cell development and beyond.
“We can get really excited about those drugs, but nobody can really predict what will happen in humans,” Liu says.
Chemical & Engineering News
ISSN 0009-2347
Copyright © 2024 American Chemical Society
You might also like...