On April 19, 2023 Circle Pharma reported that two poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held April 14-19, in Orlando, Florida, highlight promising pre-clinical data of its first-in-class orally bioavailable macrocyclic cyclin A/B inhibitors targeting intractable cancers (Press release, Circle Pharma, APR 19, 2023, View Source [SID1234630300]). Circle expects to advance its cyclin A/B inhibitor program into IND-enabling studies later this year and subsequently into clinical development for testing in a range of cancer types, including SCLC.

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The data presented by Circle Pharma shows activity across a wide range of human tumor cell lines and tumor regression in xenograft models of small cell lung carcinoma (SCLC) and ovarian cancer. Pre-clinical development of orally bioavailable macrocycles with dual cyclin A and B inhibitory activity drive synthetic lethality in multiple tumor types. The compounds are shown to be well-tolerated in mice with no observed body weight loss, neutropenia, or depletion of bone marrow across all dose regimens. In vitro studies showed that target engagement in cells leads to displacement of E2F1 from Cyclin A:CDK2 and Myt1 from Cyclin B:CDK1, and the compounds induce DNA damage, G2/M arrest, and apoptosis. The presentation further showed that sensitivity in SCLC cell lines is correlated with RB dysfunction and E2F1 target gene expression.

In addition, studies conducted by the laboratory of Matthew Oser at Dana Farber Cancer Institute (DFCI) validate that cyclin A/B inhibitors induce mitotic arrest and apoptosis in SCLC cell lines. The researchers deployed a genome wide CRISPR/Cas9 positive selection screen to identify that activation of the mitotic spindle assembly checkpoint (SAC) complex by the kinase MSP1 is a dominant mechanism for selective cancer cell killing by the cyclin A/B inhibitors. Dr. Oser’s laboratory at DFCI was sponsored by Circle Pharma.

Program Presentation Details
Cyclin A/B Abstract Number: 1559
Abstract Title: Mechanisms responsible for hypersensitivity of small cell lung cancers to novel cyclin A/B RxL macrocyclic peptide inhibitors
Session Title: Experimental and Molecular Therapeutics
Session Type: Poster

Cyclin A/B Abstract Number: 1560
Abstract Title: Orally bioavailable macrocycles that target cyclins A and B RxL motifs cause tumor regression in xenograft models and in vitro show activity across multiple cancer types
Session Title: Experimental and Molecular Therapeutics
Session Type: Poster