Pacylex Pharmaceuticals
Pacylex Pharmaceuticals, Inc...[1] is an Edmonton, Canada-based pharmaceutical company conducting clinical trials[2] of an oral, first-in-class, small molecule for the treatment of cancer. The company combines new cancer biology discovered at the University of Alberta with a family of small-molecule inhibitors developed at the University of Dundee. Pacylex is exploiting the myristoylation (NMT Inhibitor) pathway in cancer and has shown that inhibiting this pathway kills human cancer cells at drug levels far lower than those that harm normal cells (Beauchamp et al 2020).[3]
Corporate History and Milestones Pacylex was founded in 2012 by Luc Berthiaume, John R. Mackey, and Ryan Heit. Experienced biomedical executive Michael Weickert became CEO in 2017. Pacylex signed an agreement in November of 2019 with Davos Pharmaceuticals to support drug manufacturing and regulatory filings. Pacylex closed a Seed Round[4] in February of 2020. In May of 2021, a Series A round[5] was closed to fund the start of clinical trials of their first asset, PCLX-001. Pacylex remains a privately held Canadian corporation. Pacylex was selected to participate[6] in an accelerator program[7] created by Merck and the University of Alberta and received mentorship, space, and funding. Pacylex has also participated in[8] the Creative Destruction Lab (CDL)[9] 2019-2020 Health West cohort. The World’s Longest Game[10] in Edmonton, Alberta, sponsored by the Cure Cancer Foundation[11], has raised nearly $2 million CAD to support the clinical development of PCLX-001. Pacylex Pharmaceuticals began accruing patients to a Phase 1 clinical trial[12] with their lead molecule, PCLX-001, in September of 2021. The study (ClinicalTrials.gov Identifier: NCT04836195) is enrolling patients with solid tumors and Non-Hodgkin’s lymphomas. Preliminary results show pharmacokinetics suitable for once-daily oral dosing, high patient drug exposure, rapid oral absorption, and no plasma accumulation (Sangha et. al 2022[13]). No dose-limiting toxicities have been identified. Currently, patient enrollment and dosing for NHL and solid tumor patients[14] is ongoing at the following clinical sites in Canada: Princess Margaret Cancer Center in Toronto, Cross Cancer Institute in Edmonton, Centre Hospitalier de l'Université de Montréal (CHUM), and is expected to begin at British Columbia Cancer Center in Vancouver[15].
PCLX-001 and myristoylation PCLX-001 is the first NMT inhibitor[16] tested in humans. PCLX-001 is a potent small-molecule inhibitor of the two human enzymes (NMT1 and NMT2) that catalyze the process of protein N-terminal myristoylation. Myristoylation is the process where a lipid, myristate, is added to intracellular proteins as a signal for regulation[17] by promoting protein-membrane interactions. This cellular process is essential for allowing many signaling proteins to propagate signals across cell membranes. Inhibiting myristoylation disrupts the prosurvival and proliferation pathways in many cancers. Src family kinases (SFKs)[18] and several other key signaling proteins require myristoylation to function. SFKs are critically important for the cancer phenotype in Non-Hodgkin lymphoma, Acute Myelogenous Leukemia, and many solid tumors. Pacylex’s diagnostic technology can measure NMT1 and NMT2 in patients. In hematologic malignancies, loss of NMT2 is correlated with poor outcomes. If NMT levels are predictive of cancers in patients that respond to PCLX-001 treatment, then a diagnostic will be developed to identify patients most likely to respond. In human blood cancer cell lines and animals with human cancers, PCLX-001 selectively kills cancer cells deficient in NMT2. These cells are particularly sensitive to PCLX-001 which inhibits myristoylation of LYN and HGAL, key parts of the B-cell receptor (BCR) complex, thereby disrupting several Src family kinases (SFKs) and selectively inducing apoptosis (programmed cell death) in leukemia and lymphoma cells (Nature Communications 2020)[19] In many human breast cancer cell lines and animals with human cancers, PCLX-001 inhibits the growth of the cell or the tumors. It is believed that this works, at least in part, through a different mechanism than for blood cancers (Mackey et al 2021)[20]
References
- ↑ https://www.pacylex.com/. Missing or empty
|title=(help) - ↑ "Phase I Trial of PCLX-001 in Relapsed/Refractory B-cell Non-Hodgkin Lymphoma and Advanced Solid Malignancies". 28 February 2022.
- ↑ Beauchamp, Erwan; Yap, Megan C.; Iyer, Aishwarya; Perinpanayagam, Maneka A.; Gamma, Jay M.; Vincent, Krista M.; Lakshmanan, Manikandan; Raju, Anandhkumar; Tergaonkar, Vinay; Tan, Soo Yong; Lim, Soon Thye; Dong, Wei-Feng; Postovit, Lynne M.; Read, Kevin D.; Gray, David W.; Wyatt, Paul G.; MacKey, John R.; Berthiaume, Luc G. (22 October 2020). "Targeting N-myristoylation for therapy of B-cell lymphomas". Nature Communications. 11 (1): 5348. Bibcode:2020NatCo..11.5348B. doi:10.1038/s41467-020-18998-1. PMC 7582192 Check
|pmc=value (help). PMID 33093447 Check|pmid=value (help). - ↑ "Pacylex - Pacylex Raises US $3.9 Million to Advance New Cancer Therapy PCLX-001 Towards Clinical Trials".
- ↑ "Pacylex - Pacylex Pharmaceuticals Closes Series a Funding to Advance Oncology Program into the Clinic".
- ↑ "World's Longest Baseball Game raises funds for PCLX-001 development".
- ↑ "Grand Opening of Merck Accelerator in Edmonton; Pacylex one of first 4 companies accepted".
- ↑ "Pacylex Joins Creative Destruction Labs 2019/20 Health Cohort".
- ↑ [[https://www.creativedestructionlab.com Check
|url=value (help). Missing or empty|title=(help) - ↑ https://worldslongestgame.ca/. Missing or empty
|title=(help) - ↑ https://curecancerfoundation.ca/. Missing or empty
|title=(help) - ↑ "Pacylex - Pacylex Pharmaceuticals Announces the Initiation of a Phase 1 Clinical of PCLX-001, a First-in-class NMT Inhibitor, in Non-Hodgkin's Lymphomas and Solid Tumor Patients".
- ↑ Sangha, Randeep; Davies, Neal M.; Namdar, Afshin; Chu, Michael; Spratlin, Jennifer; Beauchamp, Erwan; Berthiaume, Luc G.; MacKey, John R. (March 2022). "Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma". Current Oncology. 29 (3): 1939–1946. doi:10.3390/curroncol29030158. PMC 8947478 Check
|pmc=value (help). PMID 35323358 Check|pmid=value (help). - ↑ "Pacylex - Pacylex Presents Evidence Supporting Advancement of PCLX-001 for Treatment of AML at AACR 2022".
- ↑ "Laurie Sehn | Department of Medicine".
- ↑ Beauchamp, Erwan; Yap, Megan C.; Iyer, Aishwarya; Perinpanayagam, Maneka A.; Gamma, Jay M.; Vincent, Krista M.; Lakshmanan, Manikandan; Raju, Anandhkumar; Tergaonkar, Vinay; Tan, Soo Yong; Lim, Soon Thye; Dong, Wei-Feng; Postovit, Lynne M.; Read, Kevin D.; Gray, David W.; Wyatt, Paul G.; MacKey, John R.; Berthiaume, Luc G. (22 October 2020). "Targeting N-myristoylation for therapy of B-cell lymphomas". Nature Communications. 11 (1): 5348. Bibcode:2020NatCo..11.5348B. doi:10.1038/s41467-020-18998-1. PMC 7582192 Check
|pmc=value (help). PMID 33093447 Check|pmid=value (help). - ↑ Udenwobele, D. I.; Su, R. C.; Good, S. V.; Ball, T. B.; Varma Shrivastav, S.; Shrivastav, A. (2017). "Myristoylation: An Important Protein Modification in the Immune Response". Frontiers in Immunology. 8: 751. doi:10.3389/fimmu.2017.00751. PMC 5492501. PMID 28713376.
- ↑ Parsons, Sarah J.; Parsons, J. Thomas (October 2004). "SRC family kinases, key regulators of signal transduction". Oncogene. 23 (48): 7906–7909. doi:10.1038/sj.onc.1208160. PMID 15489908. Unknown parameter
|s2cid=ignored (help) - ↑ Beauchamp, Erwan; Yap, Megan C.; Iyer, Aishwarya; Perinpanayagam, Maneka A.; Gamma, Jay M.; Vincent, Krista M.; Lakshmanan, Manikandan; Raju, Anandhkumar; Tergaonkar, Vinay; Tan, Soo Yong; Lim, Soon Thye; Dong, Wei-Feng; Postovit, Lynne M.; Read, Kevin D.; Gray, David W.; Wyatt, Paul G.; MacKey, John R.; Berthiaume, Luc G. (22 October 2020). "Targeting N-myristoylation for therapy of B-cell lymphomas". Nature Communications. 11 (1): 5348. Bibcode:2020NatCo..11.5348B. doi:10.1038/s41467-020-18998-1. PMC 7582192 Check
|pmc=value (help). PMID 33093447 Check|pmid=value (help). - ↑ MacKey, J. R.; Lai, J.; Chauhan, U.; Beauchamp, E.; Dong, W. F.; Glubrecht, D.; Sim, Y. W.; Ghosh, S.; Bigras, G.; Lai, R.; Berthiaume, L. G. (2021). "N-myristoyltransferase proteins in breast cancer: Prognostic relevance and validation as a new drug target". Breast Cancer Research and Treatment. 186 (1): 79–87. doi:10.1007/s10549-020-06037-y. PMC 7940342 Check
|pmc=value (help). PMID 33398478 Check|pmid=value (help).
Pacylex CEO Michael Weickert interviewed for CEO CFO Magazine
How a drug derived from an antiparasitic might combat blood cancer
Pacylex Pharmaceuticals at the BIO Investor Forum in San Francisco, 2019
Pacylex Pharmaceuticals completes its 'landmark' toxicology dosing
Pacylex Pharmaceuticals Closes Series A Funding to Advance Oncology Program into the Clinic
Target of new cancer treatment valid for breast as well as blood cancers: study
Pacylex Pharmaceuticals Overview- Pitchbook
Pacylex Pharmaceuticals: Medicinal Innovation Empowering Healthcare Space
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