Kang, Heejae
(2020)
Discovery of novel small molecule inhibitors of Bcl10-MALT1 interaction for the treatment of aggressive diffuse large B-cell lymphoma.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The CARMA1/Bcl10/MALT1 (CBM) signaling complex mediates antigen receptor-induced activation of the pro-survival NF-kB transcription factor in lymphocytes to support normal adaptive immunity. Gain-of-function mutations in the CARMA1 moiety or its upstream regulators trigger antigen-independent assembly of oligomeric CBM complexes, leading to constitutive activation of both the protease and scaffolding functions of MALT1, inappropriate NF-kB activity, and development of an aggressive Activated B-Cell subtype of Diffuse Large B-Cell Lymphoma (ABC DLBCL).
Since MALT1 activation relies on its recruitment to the CBM complex via its interaction with Bcl10, we sought to identify inhibitors of Bcl10-MALT1 interaction in order to target both the protease and scaffolding activities of MALT1 as a potential approach for treating ABC DLBCL. After confirming that Bcl10 residues 107-119 and the tandem Ig-like domains of MALT1 are critical for interaction, we performed a structure-guided in silico screen of 3 million compounds based on a computational model of the experimentally identified interaction interface.
Compound K691-0124 from the initial screening hits and its structural derivative, compound K691-0122, show dose-responsive inhibition of Bcl10-MALT1 interaction. Functionally, both compounds inhibit both the protease and scaffolding activities of MALT1 in Jurkat T cells, as demonstrated by its inhibition of CD3/CD28-induced RelB and N4BP1 cleavage, and inhibition of IKK phosphorylation, respectively. Both compounds also block IL2 transcription and IL-2 secretion by PMA/ionomycin-stimulated Jurkat T cells, as well as constitutive CBM-dependent secretion of IL-6 and IL-10 by ABC DLBCL cells. Accordingly, these two compounds selectively suppress the growth of ABC DLBCL cell lines, but does not affect the growth of MALT1-independent GCB DLBCL cell lines.
In conclusion, we have developed two early-stage small molecule compounds that inhibit Bcl10-MALT1 interaction, impair both protease and scaffolding activities of MALT1, inhibit secretion of cytokines encoded by MALT1-controlled downstream NF-kB target genes, and specifically inhibit proliferation of MALT1-driven ABC DLBCL cell lines. This new class of protein-protein interaction inhibitors has the potential for a more complete and efficacious blockade of MALT1, while offering protection from undesirable autoimmune side effects of unbalanced blocking of only the protease activity of MALT1, in the treatment of this aggressive form of lymphoma.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
1 June 2020 |
| Date Type: |
Publication |
| Defense Date: |
27 March 2020 |
| Approval Date: |
1 June 2020 |
| Submission Date: |
8 May 2020 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
149 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ABC DLBCL
Bcl10
drug discovery
MALT1
protein-protein interaction
small molecule drug |
| Date Deposited: |
02 Jun 2020 03:00 |
| Last Modified: |
01 Jun 2022 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38946 |
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