Kronos Bio Highlights p300 KAT Inhibition in HPV Tumors at EORTC-NCI-AACR Symposium

Kronos Bio, Inc. has released promising preclinical data regarding its p300 KAT inhibitor program for tackling tumors driven by human papillomavirus (HPV). The announcement was made at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, highlighting the potential of their inhibitor, KB-9558, in treating such cancers.

HPV integrates into regions of the human genome that are transcriptionally active, relying on p300 to express its oncogenes E6 and E7. The overexpression of these genes leads to the degradation of tumor suppressors p53 and Rb, which are crucial in controlling cell growth. Kronos Bio's data demonstrate that inhibiting the p300 KAT domain selectively represses the transcription of these oncogenes. This repression restores the p53 and Rb pathways, inducing apoptosis and reducing tumor growth.

Charles Lin, Ph.D., the Chief Scientific Officer of Kronos Bio, emphasized the critical importance of E6 and E7 in the progression of HPV-related cancers, which include head and neck, cervical, and other anogenital cancers. Lin noted the lack of approved targeted therapies for these oncogenes and highlighted the potential of p300 KAT inhibition to address this gap by targeting these viral genes and reactivating tumor suppressor pathways. The promise of KB-9558 offers a novel therapeutic approach that could significantly reduce the impact of HPV-driven cancers.

The presentation, titled "Oncogenic human papillomavirus hijacks p300 to drive viral transcription, creating a therapeutic vulnerability that can be exploited with selective p300/CBP catalytic inhibitors," outlined several key findings from their research. The integration of HPV into the human genome occurs at specific sites where p300 regulates transcription. Inhibiting p300 results in a significant reduction in the expression of HPV's E6 and E7 genes, at both the RNA and protein levels. This inhibition leads to the reactivation of p53 and Rb pathways, resulting in the upregulation of p53-activated genes like CDKN1A and the downregulation of Rb-repressed genes such as CDK1. Additionally, when E6 and E7 were reintroduced via an exogenous lentiviral vector, the effects of p300 KAT inhibition on p53 restoration and anti-tumor activity were reversed, underscoring the specificity of p300 KAT inhibition in targeting these oncogenes.

These findings support the potential therapeutic application of KB-9558 in treating HPV-driven tumors by suppressing the expression of E6 and E7 and restoring p53 activity. Kronos Bio's research underscores a significant step toward developing targeted therapies that can effectively combat HPV-driven cancers.

Kronos Bio is a clinical-stage biopharmaceutical company that focuses on creating small molecule therapeutics aimed at diseases caused by deregulated transcription, such as cancer and autoimmune conditions. The company's proprietary discovery engine identifies druggable cofactors within transcription factor regulatory networks. Kronos Bio's pipeline includes three drug candidates: Istisociclib (KB-0742), currently in a Phase 1/2 clinical trial for ovarian cancer; KB-9558, under development for multiple myeloma and HPV-driven tumors; and KB-7898, targeting Sjögren’s disease. The company operates from its headquarters in San Mateo, California, and has a research facility in Cambridge, Massachusetts.