Therapeutics Accelerator Hub Initiative Support from Dr. Mary Beckerle, CEO of Huntsman Cancer Institute (HCI), and in collaboration with HCI’s Center for Investigational Therapeutics (CIT) and College of Pharmacy, was created with the mission of bringing dedicated drug discovery and development expertise to bear on biological targets of clinical relevance under investigation by HCI and University of Utah Health Sciences faculty. Medicinal, synthetic, computational chemists, assay validation, assay development, and compound screening scientists will work in the Therapeutics Accelerator Hub and create a dedicated, multidisciplinary team with other groups on campus in order to progress the targets through the early drug discovery and development process to future clinical trials. The two phase 1 stage agents discovered in the CIT —HCI-2577/SP-2577, an LSD1 inhibitor, and HCI-2084/TP-0903, an AXL kinase inhibitor—are licensed to pharmaceutical companies.
Hari’s lab interests are in developing lead hits to drug candidates for novel targets, which include protein kinases, epigenetics, and immune-oncology targets identified by Hari’s lab members, HCI investigators, and collaborators. We have successfully employed or are employing the structure- and/or ligand-based drug design approaches to deliver compounds to clinical trials. Our Therapeutics Accelerator team led by Hari will continue to apply such approaches for drug discovery towards new targets.
Targeting Critical Immune Drivers and Epigenetic Histone Methyltransferases of Cancer
Our lab currently focuses on discovering and developing small molecule oral therapeutics for patients with significant unmet needs in oncology diseases. This currently focuses on developing highly selective small molecules that are designed to modulate both critical immune responses in the field of immune-oncology, and the histone methyltransferase family of protein targets. In its first years, our lab has rapidly discovered and has begun advancing two unique candidates each targeting stress response kinase: GCN2 (General Control Nonderepressible 2) and WDR5 (WD Repeat-containing protein 5).
Inhibition of GCN2 is mainly to restore T cell proliferation and function in nutrient-deprived conditions, to overcome immune suppression induced by myeloid-derived suppressor cells (MDSC), and to elicit antitumor responses. In the case of targeting WDR5, which plays a regulatory role mainly by constituting a core catalytic complex with MLL1 and SET1 family of proteins. This can lead to cancers, particularly leukemias and solid tumors. The WDR5 protein, though, does not have catalytic activity, but it recognizes the Win sequence of MLL1 and forms a core catalytic complex of MWRAD (MLL1, WDR5, RBBP5, ASH2L, and DYP-30) with other proteins, catalyzes H3K4 methylation, and activates gene transcription.