NU 2017-214
Inventors
Ali Shilatifard*
Zibo Zhao
Short Description
A new therapeutic approach for the treatment of acute myeloid leukemia using casein kinase inhibitors.
Background
Leukemia is a group of cancers that affects the bone marrow and results in the overproduction of dysfunctional white blood cells (WBCs). The mixed lineage leukemia (MLL) protein has been previously shown to be a key protein in the development of normal WBCs, where the expression of degradation-resistant chimeric MLLs results in the onset of many leukemias, through facilitating the expression of target oncogenes. The molecular bases for the increased stability of MLL chimeras is this loss of a cleavage site for the endopeptidase Taspase1. Through the use of a CRISPR/Cas9 targeted genome editing approach, it has been shown that knockdown of taspase1 in human cancer cell lines results in a preservation of wild-type MLLs, specifically MLL1 proteins, that results in increased association of the protein with its chromatin targets due to increased MLL1 stability, establishing taspase1 as a viable target for pharmacological intervention. Previous efforts to identify specific taspase1 inhibitors have been largely unsuccessful due to either lack of diminished proteolytic activity in response to common protease inhibitors or lack of in vivo efficacy with other developed taspase1 inhibitors.
Abstract
To address the issues with developing therapeutic strategies for the inhibition of taspase1, Northwestern researchers have developed a new approach to targeting the proteolytic effects of taspase1 through focusing on the downstream protease substrates rather than inhibiting the endopeptidase itself. Following a screen of possible targets, casein kinase II (CKII) was identified and demonstrated to induce a consistent increase in full-length MLL1 protein levels following knockdown of catalytic subunits of CKII. CX-4945, a small molecular inhibitor of CKII was identified as a highly effective inhibitor, that resulted in dose-dependent increases in full-length MLL1 proteins without having off-target effects on MLL2 and other transcription factors. Overall, this work demonstrates the validity of targeting downstream effects of the traspase1 proteolytic pathway, where pharmacological inhibition of CKII results in increased stability of the MLL1 protein, which in turn, increases its association with chromatin. This approach enables the ability to target the effects of taspase1 which has been shown to be a driver of cell proliferation and tumor progression in both leukemia and breast cancer. The approach taken in this work has broad-ranging effects in cancers caused by translocations and taspase1 overexpression and represents a key development in making taspase1 a therapeutic target for oncology drug discovery.
Applications
Treatment for MLL-rearranged leukemias, breast cancer
Development of taspase1-targeting pharmacological inhibitors for oncology drug development
Advantages
Publication
Zhao Z, Wang L, Volk A, Birch N, Stoltz K, Bartorn E, Marshall S, Rendleman E, Nestler C, Shilati J, Schiltz G, Crispino J and Shilatifard A (2018) Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia. Genes & Development. 33: 61-74.
IP Status
A US patent application has been filed.
Scheme for inhibitory targets in the taspase1 pathway. By inhibiting cleavage of MLL1 proteins, stabilization of the protein can occur, allowing for decreased cellular proliferation and tumor progression