Circle Pharma has published groundbreaking research in Nature demonstrating the robust preclinical anti-tumor activity of its first-in-class oral cyclin A/B RxL inhibitor, CID-078, which targets historically undruggable proteins to selectively kill E2F-high tumor cells. The orally bioavailable macrocycle is currently advancing through Phase 1 clinical development for patients with advanced solid tumors.
Novel Dual Mechanism Targets Cell Cycle Dysregulation
The research, conducted in collaboration with scientists from Dana-Farber Cancer Institute, Harvard Medical School, the University of Texas Southwestern Medical Center, and the University of Oxford, reveals a sophisticated dual mechanism of action. In preclinical models, cyclin A/B RxL inhibitors first blocked the cyclin A-E2F interaction, triggering aberrant sustained E2F activity, DNA damage, and replication stress. Subsequently, the inhibitors disrupted the cyclin B-Myt1 interaction, removing a critical safety brake and forcing damaged tumor cells through division, ultimately causing tumor cell death.
"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," 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.
Targeting Historically Undruggable Proteins
Cyclins A and B 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. The research demonstrates that CID-078 can potently and selectively disrupt protein-to-protein interactions between cyclins A and B and their key substrates and modulators, including E2F and MYT1.
The therapeutic approach shows particular promise for E2F-driven cancers, including nearly all small cell lung cancers, up to half of triple-negative breast cancers, and subsets of other solid tumors with RB1 alterations. Preclinical studies demonstrated the ability of cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple in vivo models, including chemotherapy-resistant SCLC patient-derived xenograft models.
Clinical Development and Platform Technology
CID-078 represents the lead program from Circle Pharma's proprietary MXMO™ platform, which overcomes key challenges in macrocycle drug development by enabling the creation of intrinsically cell-permeable and orally bioavailable therapies. A multi-center Phase 1 clinical trial (NCT06577987) is currently enrolling patients with advanced solid tumors harboring RB1 alterations.
"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."
The research highlights the potential of macrocycle therapeutics to access previously undruggable targets, offering new therapeutic possibilities for patients with difficult-to-treat cancers. Circle Pharma's approach addresses limitations of other therapeutic modalities by creating oral, cell-permeable compounds that can effectively target intracellular protein-protein interactions.
