What question did this study set out to answer?

The aim is to evaluate CID-078, a novel macrocycle inhibitor targeting cyclin A/B RxL interactions, for treating cancers with RB1 loss or hyperactivated E2F.

May 17, 2026

Abstract ND09: Discovery of CID-078, a first-in-class oral macrocycle cyclin A/B-RxL inhibitor, for the treatment of cancers with RB1 loss or hyperactivated E2F

Key Points

The aim is to evaluate CID-078, a novel macrocycle inhibitor targeting cyclin A/B RxL interactions, for treating cancers with RB1 loss or hyperactivated E2F.
Preclinical characterization of CID-078 using Circle Pharma’s MXMO™ macrocycle discovery platform.
Evaluation of drug effects on cancer cell lines with RB pathway disruption.
In vivo studies in xenograft models to assess tumor growth inhibition.
CID-078 significantly inhibits tumor growth in models with RB pathway alterations, with a consistent dose-dependent response.
Mechanistic studies show that CID-078 causes replication stress and DNA damage by hyperactivating E2F and disrupting cell-cycle regulation.
In a large panel of cancer cell lines, sensitivity correlates with elevated E2F activity and genomic alterations in the RB pathway.

Abstract

Abstract Dysregulation of the RB-E2F pathway is a hallmark of many human cancers resulting in uncontrolled transcription of genes required for DNA replication, S-phase progression, and mitotic entry. Genetic alterations that disrupt RB pathway control, such as loss of the tumor suppressor RB1, lead to hyperactivation of E2F transcriptional programs and occur across multiple tumor types. These alterations are frequently associated with aggressive disease and resistance to existing therapies. While CDK4/6 inhibitors can restore cell-cycle control in tumors with intact RB1, cancers with RB pathway disruption remain difficult to treat because few therapeutic strategies exist to exploit vulnerabilities downstream of E2F activation. Cyclins are central regulators of cell-cycle progression that activate cyclin-dependent kinases (CDKs) and recruit substrates through a conserved hydrophobic patch that binds substrates containing an RxL motif. The therapeutic potential of targeting these interactions was first demonstrated by the Kaelin laboratory at DFCI, showing that disruption of cyclin function using RxL peptides could induce hyperactivation lethality in RB1-deficient, E2F-driven cancer cells1. Subsequently, Geoff Shapiro proposed that further increasing E2F activity in tumors already characterized by high E2F signaling could push these cancers beyond a critical “tipping point, ” triggering mitotic catastrophe while sparing normal cells2. Despite their central role in cancer biology, cyclin-substrate interactions have historically been considered difficult to target pharmacologically. Here we describe the discovery and preclinical characterization of CID-078, a first-in-class orally bioavailable macrocycle inhibitor of cyclin A/B RxL substrate interactions. CID-078 was discovered using Circle Pharma’s MXMO™ macrocycle discovery platform and is designed to bind the conserved hydrophobic pocket of cyclins A and B, thereby disrupting recruitment of key cell-cycle substrates required for orderly cell-cycle progression. Structure-guided optimization produced CID-078, a conformationally constrained macrocycle inhibitor with favorable physicochemical properties and a consistent preclinical ADME/DMPK profile supporting oral development. Consistent with the tipping-point model, CID-078 selectively targets tumor cells harboring RB1 alterations that disrupt the G1/S checkpoint and drive elevated E2F activity. Mechanistic studies reveal a two-step biological mechanism underlying tumor cell killing3. Inhibition of cyclin A RxL interactions disrupts regulation of E2F during S-phase, resulting in further E2F hyperactivation, replication stress, and accumulation of DNA damage. Subsequent inhibition of cyclin B RxL interactions blocks association with the inhibitory kinase MYT1, removing negative regulation of cyclin B-CDK activity and forcing damaged tumor cells into mitosis, leading to activation of the spindle assembly checkpoint (SAC) and apoptosis. Across a large panel of cancer cell lines, sensitivity to CID-078 correlates with both transcriptional signatures of elevated E2F activity and genomic alterations that disrupt RB pathway control. Tumor types with frequent RB pathway disruption demonstrate increased sensitivity to cyclin A/B RxL inhibition. In vivo studies further demonstrate robust anti-tumor activity across multiple E2F-driven tumor models. Oral administration of CID-078 results in dose-dependent tumor growth inhibition and tumor regressions in xenograft models characterized by RB pathway disruption and elevated E2F transcriptional programs. CID-078 is currently being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors, including SCLC, sarcoma, and other RB1-altered or E2F-hyperactive cancers, to determine whether targeting cyclin substrate interactions can provide a new therapeutic strategy for tumors characterized by G1/S checkpoint disruption and elevated E2F activity. References Chen, Y. N. P. et al. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329 (1999). Shapiro, G. I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin Oncol 24, 1770-1783 (2006). Singh, S. et al. Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors. Nature 646, 734-745 (2025). Citation Format: Marie Evangelista. Discovery of CID-078, a first-in-class oral macrocycle cyclin A/B-RxL inhibitor, for the treatment of cancers with RB1 loss or hyperactivated E2F abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND09.

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