NU 2019-130

PRIMARY INVENTOR
Ali Shilatifard
 
SHORT DESCRIPTION
A series of small molecule compounds targeting the BAP1 complex for the treatment of leukemia.

BACKGROUND
ASXL1, which encodes a core component of the BAP1 histone H2A deubiquitinase complex, is one of the most frequently mutated genes in malignant myeloid diseases. Mutations of ASXL1 are associated with increased aggressiveness and poor clinical outcomes. Truncated ASXL1 stabilizes BAP1 and promotes the expression of numerous leukemia-associated genes. Chemical inhibition of BAP1 fully rescues these changes in the gene expression pattern in leukemic cells and inhibits tumor progression, suggesting inhibition of BAP1 as a new target for leukemia therapy.

ABSTRACT
Northwestern researchers have developed and synthesized a series BAP1 inhibitors following a high-throughput screen and optimization. The BAP1 inhibitors were found to selectively inhibit cells with ASXL mutations, including cells with ASXL1 point mutations that are resistant to chemo-agent treatments. In vivo studies with the lead compound, iBAP, resulted in significantly delayed disease progression in leukemic mouse models. Further optimization of this new class of small molecule inhibitors is ongoing to produce more potent compounds to inhibit BAP1 activity.

APPLICATIONS

• Therapeutics
  • Inhibitors for malignant myeloid diseases

ADVANTAGES

• Selectively binds to BAP1

PUBLICATIONS
Wang L, Birch NW, Zhao Z, Nestler CM, Kazmer A, Shilati A, Blake A, Ozark PA, Rendleman EJ, Zha D, Ryan CA, Morgan MAJ, Shilatifard A (2021). Epigenetic targeted therapy of stabilized BAP1 in ASXL1 gain-of-function mutated leukemia. Nat Cancer 2, 515-526.

IP STATUS
A US patent application has been filed.