Proteomics on detergent-enriched membrane fractions in MYC or MYCN-deregulated cancer cell models revealed that cell death is associated at least in part with loss of membrane association of mitochondrial respiratory complex I. This is concurrent with loss of myristoylation and degradation of the complex I assembly factor NDUFAF4, and induction of mitochondrial dysfunction, driven by MYC or MYCN-deregulation. NMTis eliminated or suppressed MYC- and MYCN-driven tumors in vivo without overt toxicity, suggesting that this constitutive co-translational protein modification can be targeted in MYC-driven cancers.

These findings provide robust theoretical support for the translational application of combining NMT1 inhibitors and ICB therapy in cancers under hypoxic conditions. This study introduces a combined cancer therapy strategy named "spatial blockade plus signaling inhibition of PD-L1.".

P1, N=29, Completed, Pacylex Pharmaceuticals | Recruiting --> Completed | N=60 --> 29

P1, N=35, Recruiting, Pacylex Pharmaceuticals | Not yet recruiting --> Recruiting

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.