An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient PMID: 30692685

ADC Targets in Oncology

2026-04-10

An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient

Nat Chem Biol. 2019 Mar;15(3):304-313. doi: 10.1038/s41589-018-0222-1.

Jean Quancard ¹ , Theo Klein ² ³ ⁴ ⁵ , Shan-Yu Fung ⁶ ⁷ , Martin Renatus ⁸ , Nicola Hughes ⁸ , Laura Israël ⁸ , John J Priatel ⁶ ⁹ , Sohyeong Kang ⁶ ⁹ , Michael A Blank ¹⁰ ¹¹ , Rosa I Viner ¹⁰ , Jutta Blank ⁸ , Achim Schlapbach ⁸ , Paul Erbel ⁸ , Jayachandran Kizhakkedathu ⁴ ⁹ , Frédéric Villard ⁸ , René Hersperger ⁸ , Stuart E Turvey ⁶ ⁷ , Joerg Eder ⁸ , Frédéric Bornancin ¹² , Christopher M Overall ¹³ ¹⁴ ¹⁵

Affiliations

1. Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland. [email protected].
2. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
3. Department of Oral Biological and Medical Science, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.
4. Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
5. Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, Netherlands.
6. Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
7. BC Children's Hospital, Vancouver, British Columbia, Canada.
8. Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
9. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
10. Thermo Fisher Scientific, San Jose, CA, USA.
11. AbbVie Biotherapeutics, Inc., Redwood City, CA, USA.
12. Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland. [email protected].
13. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].
14. Department of Oral Biological and Medical Science, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].
15. Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].

Abstract

MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation. We discovered nanomolar, selective allosteric inhibitors of MALT1 that bind by displacing the side chain of Trp580, locking the protease in an inactive conformation. Interestingly, we had previously identified a patient homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. We show that the loss of tryptophan weakened interactions between the paracaspase and C-terminal immunoglobulin MALT1 domains resulting in protein instability, reduced protein levels and functions. Upon binding of allosteric inhibitors of increasing potency, we found proportionate increased stabilization of MALT1-W580S to reach that of wild-type MALT1. With restored levels of stable MALT1 protein, the most potent of the allosteric inhibitors rescued NF-κB and JNK signaling in patient lymphocytes. Following compound washout, MALT1 substrate cleavage was partly recovered. Thus, a molecular corrector rescues an enzyme deficiency by substituting for the mutated residue, inspiring new potential precision therapies to increase mutant enzyme activity in Other deficiencies.