NU 2022-081

INVENTORS

• Sarki Abdulkadir (PI)*
• Gary Schiltz (PI)*

SHORT DESCRIPTION

A small molecule PROTAC technology that degrades DOT1L protein for targeted treatment of leukemia and prostate cancer.

BACKGROUND

Current cancer treatments, especially for MLL-rearranged leukemia and prostate cancer, face challenges of off-target effects and systemic toxicity. Existing therapies often lack selectivity and may induce severe side effects. This creates an unmet need for more precise treatment options that directly target tumorigenic pathways while sparing normal cells.

ABSTRACT

Northwestern researchers developed small molecule proteolysis-targeting chimeric molecules (PROTACs) designed to degrade the DOT1L protein. Our compounds recruit an E3 ubiquitin ligase to DOT1L, which leads to its ubiquitination and subsequent degradation. The PROTACs show potent anti-proliferative effects at sub-micromolar concentrations in cancer cell lines, particularly in MLL-rearranged leukemia and DOT1L-overexpressing prostate cancer models. This technology provides a new targeted approach to disrupt oncogenic signaling pathways by eliminating a key regulatory protein.

DEVELOPMENT STAGE

TRL-4 - Prototype Validated in Lab: The PROTAC compounds have been synthesized and demonstrated effective DOT1L degradation in laboratory models at sub-micromolar concentrations.

APPLICATIONS

• Treatment of MLL-rearranged leukemia: Offers targeted intervention for acute leukemias.
• Treatment of DOT1L-overexpressing prostate cancer: Provides precision therapy for aggressive prostate cancer.
• Broader cancer applications: Potential to address various cancers driven by DOT1L dysregulation.
• Therapeutic research tool: Serves as a platform to study targeted protein degradation mechanisms.

ADVANTAGES

• Minimizes off-target effects: Selectively degrades DOT1L to reduce systemic toxicity.
• Potent anti-proliferative activity: Demonstrates efficacy at sub-micromolar concentrations.
• Broad therapeutic potential: Applicable to multiple cancer types driven by DOT1L dysregulation.
• Novel mechanism of action: Employs targeted protein degradation to tackle previously undruggable targets.

PUBLICATIONS

• Sarki Abdulkadir, Gary Schiltz et al. Small molecule degraders of DOT1L and uses thereof US Patent, 2024

IP STATUS US Patent Pending

CATEGORY/INDUSTRY PIPELINE Therapeutics

KEYWORDS PROTAC, DOT1L degradation, targeted cancer therapy, leukemia, prostate cancer, protein degradation, precision medicine, small molecule degraders