Ari M. Melnick, Gebroe Family Professor of Hematology/Oncology
Technology Summary
Four lead compounds that inhibit MALT1 protease for the treatment of B cell lymphomas. Two have been tested in mouse models of diffuse large B-cell lymphoma (DLBCL).
Market Overview
DLBCL accounts for around a third of all non-Hodgkin lymphomas; between 2011 and 2015 the incidence in the US was 5.5 per 100,000 per year, and the number of deaths was 1.8 per 100,000/year. There is a 5 year survival rate of around 60%. The median age of onset is around 60. The standard treatment is chemotherapy + rituximab, followed by radiation therapy if necessary. A CAR-T therapy by Kite was approved in 2017 for refractory DLBL. There were 350 DLBCL interventional clinical trials underway as of December 2018.
A 2018 study found that first and second line treatments for DLBCL cost the health care system around $200K/patient, and lifetime treatment of refractory patients approaches $1M.
Technology Overview
MALT1 is a protease that is part of an oncogenic complex that activates NF-κB pathways in B cell lymphomas. There are no MALT1-inhibiting drugs on the market.
The Melnick lab and its collaborators have developed four lead compounds from discovery campaigns.
One is a peptide-mimetic compound that irreversibly inhibits MALT1. It inhibits the growth of the OCI-Ly3 DLBL cancer cell line by decreasing proliferation and increasing apoptosis. It suppressed growth of DLBCL patient-derived xenografts ex vivo and was efficacious in vivo against DLBCL xenografted tumors in mice. It has a half-life of 4.3 hours in whole mouse blood. (D-7251)
Another lead uses PROTAC chemistry, targeting both MALT1 and an E3 ubiquitin ligase, labeling MALT1 for degradation by the ubiquitin proteasome system. These have been tested in the OCI-Ly3 cell line. (D-7556)
The third and fourth are allosteric inhibitors of MALT1, one a quinoline and the other a thiazolopyridine. Both are potent, with IC50 values of 10 nM and 13 nM, respectively. They have been tested on the OCI-Ly3 cell line and initial pharmacokinetics and pharmacodynamics have been evaluated in mice. (D-7602)
Publications
Resources
Intellectual Property
Patents:
- US Patent: 9,592,223: "Small molecule inhibitors of MALT1" (Issued March 14, 2017)
- EP Patent: 2,916,656: "Small molecule inhibitors of malt1" (IssuedOctober 25th, 2017)
- US Patent: 10,689,366: "Compounds for MALT1 degradation" (Issued June 23, 2020)
- JP Patent: JP7097880B2: "Compounds for MALT1 degradation" (Issued July 8, 2022)
- US Patent: 10,711,036: "MALT1 Inhibitors and uses thereof" (Issued July 14, 2020)(Additional issued patents in FR, DE, IE, GB)
- US Patent: 11,248,007: "Inhibitors of MALT1 and uses thereof" (Issued February 15, 2022)
Cornell Reference:
- 7602, 7251 and 7556
Contact Information
For additional information please contact
Brian Kelly
Director, Business Development and Licensing
Phone: (646) 962-7041
Email: bjk44@cornell.edu