P1, N=35, Not yet recruiting, Pacylex Pharmaceuticals

This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis N-myristoyltransferase-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas.

P1, N=60, Recruiting, Pacylex Pharmaceuticals | Trial primary completion date: Feb 2024 --> Oct 2024

Zelenirstat (PCLX-001) is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins (IC 50 of 5nM and 8nM, respectively)...Additional pts, including a phase IIA study in pts with R/R B-cell NHL, are accruing at this dose for further safety and activity exploration. The absence of severe toxicities, attainment of plasma concentrations highly active in preclinical models, and early evidence of antitumor activity support the ongoing development of zelenirstat for pts with R/R B-cell lymphomas and advanced solid tumors.

P1, N=60, Recruiting, Pacylex Pharmaceuticals | Trial completion date: Jul 2024 --> Oct 2024 | Trial primary completion date: Jun 2023 --> Feb 2024

Inhibitory efficacy on N-myristoyltransferase activity by d-NMAPPD is stereospecific. (1R,2R)-LCL204 reduced global N-myristoylation and androgen receptor protein levels at low micromolar concentrations in prostate cancer cells. pharmacological inhibition of NMT1 enhances ubiquitin-mediated proteasome degradation of AR. This study illustrates a novel function of N-myristoyltransferase and provides a potential strategy for treatment of CRPC.

By inhibiting this essential protein modification process, PCLX-001 shows high therapeutic potential in multiple cancer cell lines and animal models...The PCLX sensitivity score–91 (PSS-91) is higher in sensitive tumors compared to their associated normal tissue, in hematological cancers and in highly metabolically active tumors.ConclusionPCLX-001 is a drug that preferentially targets select tumor types in a manner reminiscent of synthetic lethality. In-depth analysis of sensitive cells allowed us to develop a PSS-91 sensitivity signature that will help identify future cancer indications and patients that would benefit from N-myristoyltransferase inhibitor therapy.

P1, N=60, Recruiting, Pacylex Pharmaceuticals | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Feb 2023 --> Jun 2023

In aggregate, our preclinical observations suggest that PCLX-001 is highly potent against AML cells in vitro and in vivo (both circulating and in the bone marrow), and, that LSCs are also more sensitive to PCLX-001 than non-leukemic stem cells. This further supports the initiation of PCLX-001evaluation in AML clinical trials scheduled to start in late 2022.

P1, N=60, Recruiting, Pacylex Pharmaceuticals | Trial completion date: Mar 2023 --> Jul 2023 | Trial primary completion date: May 2022 --> Feb 2023

PCLX-001 preferentially targeted AML cells inducing apoptosis and reducing leukemic burden. These findings validate NMT inhibition as a novel therapeutic strategy for AML and warrant the evaluation of PCLX-001 in clinical trials for adult AML.

Data from the TCGA Transcriptome database showed high NMT1 and low NMT2 were associated with reduced overall and event-free survival in adult AML, and high NMT1 - but not NMT2 - expression is associated with proliferative gene sets in AML cell lines. AML cell lines treated with PCLX-001 showed a significant reduction in total protein myristoylation, as well as reduced levels of SFK proteins and SFK phosphorylation. PCLX-001 induced apoptosis in AML cell lines and patient blasts at concentrations which spared a large proportion of peripheral blood lymphocytes and monocytes from healthy individuals.

P1, N=60, Recruiting, Pacylex Pharmaceuticals | Trial completion date: Dec 2022 --> Mar 2023

P1, N=60, Recruiting, Pacylex Pharmaceuticals | Not yet recruiting --> Recruiting

P1, N=60, Not yet recruiting, Pacylex Pharmaceuticals