Research uncovers how inhibiting interactions between cyclin A and cyclin B and their key binding partners, E2F and MYT1, selectively kills E2F-high tumor cells
Circle Pharma’s oral first-in-class cyclin A/B RxL inhibitor program, CID-078, is advancing in Phase 1 clinical development for patients with advanced solid tumors
Publication underscores potential of Circle Pharma’s MXMO™ platform to enable creation of oral, cell-permeable macrocycle therapies, including for historically undruggable targets such as cyclins, with applicability across significant cancer patient populations
Circle Pharma, Inc., a clinical-stage biopharmaceutical company pioneering next-generation targeted macrocycle therapeutics for difficult-to-treat cancers, today announced a Nature publication describing robust pre-clinical tumor suppression and novel mechanistic insights from inhibiting the binding of certain protein substrates (that bind via RxL motifs) to cyclins A and B in E2F-high tumor cells. Circle Pharma’s oral cyclin A/B RxL inhibitor, CID-078, is a first-in-class, orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that is being evaluated in a Phase 1 clinical trial for patients with advanced solid tumors.
Cyclins (including cyclins A and B) are a family of proteins that function as master regulators of the cell cycle by binding to and activating their catalytic partners, the cyclin-dependent kinases (CDKs). Cancers driven by high E2F activity, such as small cell lung cancer (SCLC) and other tumors with RB1 alterations, have an overactive cell cycle that leads to uncontrolled tumor cell proliferation. In preclinical models, cyclin A/B RxL inhibitors:
- Blocked the cyclin A-E2F interaction, triggering aberrant sustained E2F activity, DNA damage, and replication stress.
- Subsequently disrupted the cyclin B-Myt1 interaction, removing a critical safety brake and forcing damaged tumor cells through division, causing tumor cell death.
- Produced robust anti-tumor activity, including in chemotherapy-resistant SCLC patient-derived xenograft models.
The publication, which was co-authored by scientists from Circle Pharma and the Dana-Farber Cancer Institute, Harvard Medical School, the University of Texas Southwestern Medical Center, and the University of Oxford, can be accessed here (doi: 10.1038/s41586-025-09433-w).
“We are excited to have the novel biology and compelling anti-cancer effects of the cyclin A/B RxL inhibitors developed at Circle recognized within the broader scientific community through this publication in Nature,” said David J. Earp, J.D., Ph.D., president and chief executive officer of Circle Pharma. “This work underscores the capabilities of our MXMO™ platform to generate oral, cell-permeable macrocycle therapies, such as CID-078, including for historically undruggable targets such as cyclins. With our first-in-human Phase 1 study of CID-078 well underway, we are eager to see the innovative research outlined in this publication translate into new, high-impact therapeutic options for people living with cancer.”
“These findings build upon previous work and reveal additional gain-of-function mechanisms through which cyclin A/B RxL inhibition triggers apoptosis in cancer cells, further supporting this approach for E2F-driven cancers, such as cancers with RB1 alterations, which includes nearly all SCLCs, up to half of triple-negative breast cancers, and subsets of other solid tumors,” said Matthew G. Oser, M.D., Ph.D., senior author of the publication and associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School. “Circle Pharma’s cell-permeable, oral macrocycles are designed to overcome the limitations of other therapeutic modalities and are ideally positioned to access cyclins and other historically undruggable targets, offering exciting potential for patients with cancer.”
