B-cell lymphoma might respond to N-myristoyltransferase inhibition

Reuters Health - 26/11/2020 - Targeting N-myristoylation might prove to be an effective treatment for B-cell lymphoma and other cancers, according to a preclinical study.

Myristoylation, the N-terminal modification of proteins mediated by N-myristoyl-transferase (NMT), plays a key role in cell signaling and allows for dynamic interactions of proteins with cell membranes. NMT expression levels and activity are increased in some cancers.

Dr. Luc G. Berthiaume of the University of Alberta and Pacylex Pharmaceuticals Inc., in Edmonton, Canada, and colleagues tested the sensitivity of 300 cancer cell lines encompassing all major cancer types to NMT inhibition with the orally bioavailable small-molecule inhibitor PCLX-001.

PCLX-001 inhibited the viability and growth of nearly all types of cancer cell lines tested, but it inhibited hematological cancer cells in vitro more effectively than it did other cancer cell types or select normal cells, the researchers report in Nature Communications.

Moreover, PCLX-100 preferentially inhibited myristoylation in malignant lymphoma cells, in comparison to normal immortalized B cells, leading to selective cell death.

In a mouse B-cell lymphoma model, PCLX-001 treatment was associated with dose-dependent reductions in NMT activity and prolonged survival.

Moreover, PCLX-001 treatment induced apoptosis and cell-cycle arrest in a dose-specific manner in a patient-derived diffuse large B-cell lymphoma (DLBCL).

In separate experiments, mice tolerated PCLX-001 at doses that caused 100% tumor regression in the mouse lymphoma model.

"Altogether, our results demonstrate that PCLX-001 treatment inhibits the growth of lymphomas in vivo, including the complete regression of disease refractory to other clinically approved treatments and thus establishes a proof-of-concept for the use of a bona fide NMT inhibitor such as PCLX-001 in cancer,” the authors conclude.

“These findings support the ongoing development and potential clinical trials of PCLX-001 and related NMT inhibitors as therapies for B-cell lymphoma and possibly other cancers,” they add.

Several authors are cofounders of Pacylex Pharmaceuticals Inc., which owns the rights to related patent applications.

Dr. Berthiaume did not respond to a request for comments.

SOURCE: https://go.nature.com/31JmFXV Nature Communications, online October 22, 2020.

By Reuters Staff



Posted on 26 November 20203 December 2020