N-myristoyltransferase inhibitors

Short description: Investigational drug

N-myristoyltransferase inhibitors are small molecules that target and inhibit N-myristoyltransferases, which block the addition of myristic acid to the penultimate glycine of proteins with myristoylation signal. The prototype is the DDD85646,^[1] and the analogues IMP-1088 and zelenirstat (PCLX-001). N-myristoyltransferase inhibitors have been shown to have potent antiviral and anti-neoplastic activities.^[2]^[3]^[4]^[5]

References

↑ "RCSB PDB - 3IWE: Crystal Structure of human type-I N-myristoyltransferase with bound myristoyl-CoA and inhibitor DDD85646" (in en-US). https://www.rcsb.org/structure/3IWE.
↑ Witwit, Haydar; Cubitt, Beatrice; Khafaji, Roaa; Castro, Esteban M.; Goicoechea, Miguel; Lorenzo, Maria M.; Blasco, Rafael; Martinez-Sobrido, Luis et al. (January 13, 2025). "Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance" (in en). Viruses 17 (1): 92. doi:10.3390/v17010092. ISSN 1999-4915.
↑ Witwit, Haydar; Betancourt, Carlos Alberto; Cubitt, Beatrice; Khafaji, Roaa; Kowalski, Heinrich; Jackson, Nathaniel; Ye, Chengjin; Martinez-Sobrido, Luis et al. (August 26, 2024). "Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication" (in en). Viruses 16 (9): 1362. doi:10.3390/v16091362. ISSN 1999-4915. PMID 39339839.
↑ Gamma, Jay M.; Liu, Qiang; Beauchamp, Erwan; Iyer, Aishwarya; Yap, Megan C.; Zak, Zoulika; Ekstrom, Cassidy; Pain, Rony et al. (2025-01-02). "Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signaling and Oxidative Phosphorylation, Killing Acute Myeloid Leukemia Cells" (in en). Molecular Cancer Therapeutics 24 (1): 69–80. doi:10.1158/1535-7163.MCT-24-0307. ISSN 1535-7163. PMID 39382188.
↑ Sangha, Randeep; Jamal, Rahima; Spratlin, Jennifer; Kuruvilla, John; Sehn, Laurie H.; Beauchamp, Erwan; Weickert, Michael; Berthiaume, Luc G. et al. (August 2024). "A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas" (in en). Investigational New Drugs 42 (4): 386–393. doi:10.1007/s10637-024-01448-w. ISSN 0167-6997. PMID 38837078.

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[1] "RCSB PDB - 3IWE: Crystal Structure of human type-I N-myristoyltransferase with bound myristoyl-CoA and inhibitor DDD85646" (in en-US). https://www.rcsb.org/structure/3IWE.

[2] Witwit, Haydar; Cubitt, Beatrice; Khafaji, Roaa; Castro, Esteban M.; Goicoechea, Miguel; Lorenzo, Maria M.; Blasco, Rafael; Martinez-Sobrido, Luis et al. (January 13, 2025). "Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance" (in en). Viruses 17 (1): 92. doi:10.3390/v17010092. ISSN 1999-4915.

[3] Witwit, Haydar; Betancourt, Carlos Alberto; Cubitt, Beatrice; Khafaji, Roaa; Kowalski, Heinrich; Jackson, Nathaniel; Ye, Chengjin; Martinez-Sobrido, Luis et al. (August 26, 2024). "Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication" (in en). Viruses 16 (9): 1362. doi:10.3390/v16091362. ISSN 1999-4915. PMID 39339839.

[4] Gamma, Jay M.; Liu, Qiang; Beauchamp, Erwan; Iyer, Aishwarya; Yap, Megan C.; Zak, Zoulika; Ekstrom, Cassidy; Pain, Rony et al. (2025-01-02). "Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signaling and Oxidative Phosphorylation, Killing Acute Myeloid Leukemia Cells" (in en). Molecular Cancer Therapeutics 24 (1): 69–80. doi:10.1158/1535-7163.MCT-24-0307. ISSN 1535-7163. PMID 39382188.

[5] Sangha, Randeep; Jamal, Rahima; Spratlin, Jennifer; Kuruvilla, John; Sehn, Laurie H.; Beauchamp, Erwan; Weickert, Michael; Berthiaume, Luc G. et al. (August 2024). "A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas" (in en). Investigational New Drugs 42 (4): 386–393. doi:10.1007/s10637-024-01448-w. ISSN 0167-6997. PMID 38837078.

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N-myristoyltransferase inhibitors

Topic: Chemistry

References