ASH1L degradation as a new treatment for acute leukemia
Jolanta Grembecka
PhDRegents of the University of Michigan
Project Term: July 1, 2019 - December 31, 2023
This project is focused to develop small molecule degraders of ASH1L histone methyltransferase as a treatment for aggressive sub-types of AML and ALL with high expression of HOXA genes by utilizing the PROTAC (proteolysis targeting chimera) approach. Optimization of ASH1L degraders and their comprehensive evaluation in in vitro and in vivo leukemia models are proposed. We expect these studies will lead to new therapeutics for aggressive acute leukemias with high HOXA expression.
Acute Myeloid Leukemia (AML) patients have very poor prognosis with currently available treatments and over 10,500 people are expected to die from AML in US in 2017, emphasizing the critical need for new therapies for these patients. AMLs with high expression of the Homeobox (HOX) genes, in particular with upregulation of HOXA9 gene, belong to the most aggressive AML sub-types that urgently need therapeutic intervention. High level of HOXA genes is also implicated in the T-cell acute lymphoblastic leukemia (ALL). Therefore, small molecules that reduce the expression level of HOXA genes might represent a novel promising treatment strategy for AML and ALL patients, both children and adults. We and others have identified ASH1L histone methyltransferase as an important therapeutic target in AMLs with high HOXA expression. Importantly, loss of Ash1L did not affect normal hematopoiesis in mice in the steady-state conditions, supporting a therapeutic window for ASH1L inhibitors. To this end, we applied a PROTAC (proteolysis targeting chimera) approach and developed compounds that induce degradation of ASH1L protein. When tested in leukemia cells, these compounds lead to growth arrest, differentiation and downregulation of HOXA genes in AML and ALL cell lines. In this project, we will continue optimization of our PROTAC degraders of ASH1L to improve their potency and drug-like properties, including pharmacokinetic profile and solubility. Moreover, we will assess the activity of our new PROTAC molecules in leukemia cell lines and in in vivo models of AML and ALL, including patient derived xenografts. This work will help to establish the sub-types of AML and ALL susceptible to ASH1L degradation and should result in new therapeutic agents for aggressive acute leukemia with high expression of HOXA genes.