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Discovery of an LSD1 PROTAC degrader
Amir Hosseini1, Xing Qiu2,3,4, Yan Xiong2,3,4
1Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
Abstract:
Aberrant expression of lysine-specific demethylase 1 (LSD1) has been implicated in various cancers, including acute myeloid leukemia (AML). Recent studies have revealed both catalytic and noncatalytic oncogenic functions of LSD1, which cannot be effectively addressed by traditional small-molecule inhibitors. Therefore, to remove LSD1 and mitigate its oncogenic activity, we utilized the proteolysis-targeting chimera (PROTAC) approach and developed an LSD1 PROTAC degrader MS9117, which recruits the E3 ligase cereblon (CRBN). MS9117 induces LSD1 degradation in a concentration-, time-, CRBN-, and proteasome-dependent manner. Importantly, MS9117 effectively degrades LSD1 and demonstrates superior antiproliferative effects in AML cells, compared to the existing pharmacological LSD1 inhibitors. Furthermore, MS9117 also sensitized nonacute promyelocytic leukemia AML cells to all-trans retinoic acid treatment. Moreover, we developed two negative controls of MS9117, MS9117N1 and MS9117N2, which do not degrade LSD1 or inhibit leukemia cell growth, further confirming the mechanism of action of MS9117. Overall, MS9117 serves as a valuable chemical tool and a potential therapeutic to target both the catalytic and scaffolding functions of LSD1. With several LSD1 inhibitors already in clinical development, the LSD1 degraders such as MS9117 offer an additional option for future clinical studies.
Insights
A novel proteolysis-targeting chimera (PROTAC) degrader, MS9117, effectively eliminates lysine-specific demethylase 1 (LSD1) in acute myeloid leukemia (AML) cells, showing superior antiproliferative effects compared to current inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Aberrant lysine-specific demethylase 1 (LSD1) expression is linked to various cancers, notably acute myeloid leukemia (AML).
- LSD1 possesses both catalytic and noncatalytic oncogenic functions, challenging traditional small-molecule inhibitor efficacy.
- Existing inhibitors do not fully address the multifaceted oncogenic roles of LSD1.
Purpose of the Study:
- To develop a novel therapeutic strategy targeting LSD1's oncogenic functions.
- To create a proteolysis-targeting chimera (PROTAC) degrader for LSD1.
- To evaluate the efficacy and mechanism of action of the developed LSD1 PROTAC, MS9117, in AML models.
Main Methods:
- Development of MS9117, an LSD1 PROTAC degrader recruiting the E3 ligase cereblon (CRBN).
- Assessment of MS9117-induced LSD1 degradation in AML cells, examining concentration, time, CRBN, and proteasome dependence.
- Comparative analysis of MS9117's antiproliferative effects against existing pharmacological LSD1 inhibitors in AML cells.
- Evaluation of MS9117's impact on sensitizing AML cells to all-trans retinoic acid (ATRA).
- Utilized negative control compounds (MS9117N1, MS9117N2) to confirm mechanism of action.
Main Results:
- MS9117 effectively induces LSD1 degradation in a CRBN- and proteasome-dependent manner.
- MS9117 exhibits superior antiproliferative activity in AML cells compared to current LSD1 inhibitors.
- MS9117 enhances the sensitivity of nonacute promyelocytic leukemia AML cells to ATRA.
- Negative controls confirmed the specificity of MS9117's mechanism.
Conclusions:
- MS9117 is a potent chemical tool and potential therapeutic for targeting both catalytic and scaffolding functions of LSD1.
- LSD1 PROTAC degraders like MS9117 offer a promising alternative therapeutic strategy for AML.
- MS9117 warrants further investigation for clinical applications in AML treatment.
