Revolver Tx is developing novel peptide-based inhibitors of transcription factors, which were previously thought to be intractable drug targets, yet are critical to the proliferation of cancer cells. Our project is focused on identifying functional inhibitors capable of removing transcription factors from DNA, optimising these and conducting preclinical efficacy and toxicity studies ready for clinical trials. Consequently, Revolver is focused on drugging previously "undruggable" transcription factors. Our initial therapeutic focus in on cancer. This proposal is focused on screening transcription factors strongly associated with childhood brain cancers termed gliomas. We are collaborating with Professor Chris Jones, Professor of Childhood Brain Tumour biology at the Institute of Cancer Research. Professor Jones has identified two key sets of transcription factors, AP-1 and DLX 1-6, which are strongly implicated in two types of glioma: **_(i)_** Diffuse midline glioma, H3K27-altered (DMG-H3K27); and _**(ii)**_ Diffuse hemispheric glioma, H3G34-mutant. There are no current treatments for these gliomas which are almost invariably fatal. Revolver already has lead peptides targeting the first transcription factor, AP-1, which can immediately progress into preclinical testing in patient samples of DMG-H3K27 held by ICR. For the DLX 1-6 targets we will build peptide libraries and screen these using Revolver's platform technology to identify peptide inhibitors. These will then be tested in patient samples of DHG-H3G34 by ICR. The output of the project will be two-fold **_i)_** new peptide drugs for the treatment of two currently untreatable childhood cancers and **_ii)_** a validated platform technology within Revolver Therapeutics. These can both be leveraged to secure further investment to develop the compounds for the benefit of cancer patients. Whilst these cancers are small markets we are already in discussion with LifeArc for the further funding of these programmes if we secure initial data.

Revolver Tx is developing novel peptide-based inhibitors of transcription factors, which were previously thought to be intractable drug targets and are critical to the proliferation of cancer cells. Our project is focused on evaluating a functional inhibitor capable of removing transcription factors from DNA by conducting preclinical efficacy studies to validate our technology platform. Consequently, Revolver Peptides are focused on drugging "undruggable" transcription factors by using engineering biology technology. Our initial therapeutic focus is on cancer. According to the World Health Organisation, cancer is a leading cause of death worldwide and accounted for nearly 10 million deaths in 2020, with the number of new cancer cases is expected to rise by 70% over the next two decades. In the UK, there are more than 360,000 new cancer cases every year, which is 990 every day. Every two minutes someone in the UK is diagnosed with cancer. Although historic investment in research has resulted in cancer survival rates improving, not all forms of the disease have seen such progress, and, for some cancers, long-term survival rates have not changed for decades. Consequently, there is an urgent need for a robust platform to transform drug screening, leading to improvements over current treatment options. Across the pharmaceutical industry, potential new cancer drugs dominate their pipeline, comprising at least one third of all drugs currently in development, which has continued to grow each year. Almost 7,000 new cancer products were in development globally, double the total of the next largest therapeutic area. We believe the pharmaceutical industry's appetite for differentiated early-stage cancer assets will continue to grow for at least the next five years and, probably, well beyond. Fed by these unprecedented levels of investment, the pharmaceutical industry remains hungry for truly differentiated drug discovery programmes and their underpinning platform technologies. Consequently, pharmaceutical companies continue to adopt a strategic approach to the outsourcing of innovative R&D requirements to specialist partners by in licensing of early-stage therapeutic products. This established strategy is motivated by the observation that current internal drug pipelines are failing to meet the expected growth demands for discovering cost-effective new therapies without supplementing this with externally sourced innovation. The vision for Revolver is to become a global market leader in providing drug discovery solutions and early-stage therapeutic assets to the pharmaceutical industry by commercially exploiting unique protein-DNA screens generating Revolver Peptides as research tools to enable the discovery of innovative new therapeutics.