Development of new Malt1 inhibitors and probes
Bo-Tao Xin1, Gisela Schimmack2, Yimeng Du1
1Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
Abstract:
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) is a promising therapeutic target for the treatment of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Several research groups have reported on the development of Malt1 inhibitors and activity-based probes for in vitro and in situ monitoring and modulating Malt1 activity. In this paper, we report on two activity-based Malt1 probes (6 and 7) and a focused library of 19 new Malt1 inhibitors. Our peptide-based probe 6 labels Malt1 in an activity-based manner. In contrast, probe 7, derived from the known covalent inhibitor MI-2, labels both wild type and catalytically inactive Cys to Ala mutant Malt1, suggesting that MI-2 inhibits Malt1 by reacting with a nucleophilic residue other than the active site cysteine. Furthermore, two of our inhibitors (9, apparent IC50 3.0μM, and 13, apparent IC50 2.1μM) show good inhibitory activity against Malt1 and outperform MI-2 (apparent IC50 7.8μM) in our competitive activity-based protein profiling assay.
Insights
New Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) inhibitors and activity-based probes were developed. Two inhibitors demonstrated potent Malt1 inhibition, outperforming existing compounds in assays for activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL) treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) is a key target in activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL).
- Development of Malt1 inhibitors and activity-based probes is crucial for therapeutic strategies.
- Existing probes and inhibitors require further characterization and optimization.
Purpose of the Study:
- To design and synthesize novel Malt1 inhibitors and activity-based probes.
- To investigate the inhibitory mechanism of a known Malt1 inhibitor (MI-2).
- To evaluate the efficacy of new inhibitors against Malt1 activity.
Main Methods:
- Synthesis of two Malt1 activity-based probes (6 and 7).
- Creation of a focused library of 19 Malt1 inhibitors.
- Activity-based protein profiling assays to assess inhibitor potency and mechanism.
Main Results:
- Probe 6 successfully labeled Malt1 in an activity-based manner.
- Probe 7 indicated that MI-2 inhibits Malt1 via a non-active site cysteine residue.
- Two novel inhibitors (9 and 13) exhibited potent Malt1 inhibition (IC50 values of 3.0μM and 2.1μM, respectively), outperforming MI-2 (IC50 7.8μM).
Conclusions:
- Novel Malt1 inhibitors and activity-based probes have been successfully developed.
- The findings provide insights into the inhibition mechanism of MI-2.
- The developed inhibitors show significant therapeutic potential for ABC-DLBCL treatment.
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