PAC-1

This article refers to the anti-tumor molecule, and not the a2iib3 integrin activation specific antibody of the same name

PAC-1
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ECHA InfoCard 100.164.322 Edit this at Wikidata
Chemical and physical data
Formula C23H28N4O2
Molar mass 392.494 g/mol
3D model (JSmol)
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PAC-1 (first procaspase activating compound) is a synthesized chemical compound that selectively induces apoptosis, in cancerous cells. It was granted orphan drug status by the FDA in 2016.

History

PAC-1 was discovered in Professor Paul Hergenrother's laboratory at the University of Illinois at Urbana-Champaign during a process that screened many chemicals for anti-tumor potential. This molecule, when delivered to cancer cells, signals the cells to self-destruct by activating an "executioner" protein, procaspase-3. Then, the activated executioner protein begins a cascade of events that destroys the machinery of the cell. In 2011, Vanquish Oncology Inc. was founded to move PAC-1 forward to a human clinical trial. In 2013, Vanquish announced a multimillion-dollar angel investment into the company. In 2015, a phase I clinical trial of PAC-1 opened for enrollment of cancer patients, and in 2016, it was announced that PAC-1 had been granted Orphan Drug Designation for treatment of glioblastoma by the FDA, and in late 2017 a Phase 1b trial began of PAC-1 plus temozolomide for treatment of patients with recurrent glioblastoma or anaplastic astrocytoma.

Mechanism of action

In cells, the executioner protein, caspase-3, is stored in its inactive form, procaspase-3. This way, the cell can quickly undergo apoptosis by activating the protein that is already there. This inactive form is called a zymogen. Procaspase-3 is known to be inhibited by low levels of zinc. PAC-1 activates procaspase-3 by chelating zinc, thus relieving the zinc-mediated inhibition. This allows procaspase-3 to be an active enzyme, and it can then cleave another molecule of procaspase-3 to active caspase-3. Caspase-3 can further activate other molecules of procaspase-3 in the cell, causing an exponential increase in caspase-3 concentration. PAC-1 facilitates this process and causes the cell to undergo apoptosis quickly.[1]

This direct procaspase-3 activation mode-of-action for PAC-1 has been confirmed by other laboratories: In 2013 by the Megeney lab during the course of studies on the role of caspase-3 in cardiomyocytes,[2] in 2014 by the Wu lab in an extensive study on the anticancer activity and mode-of-action of PAC-1 and derivatives,[3] and in 2015 by the Gandhi lab in an exploration of the potential of PAC-1 and derivative B-PAC-1 for treatment of chronic lymphocytic leukemia (CLL).[4]

A potential selectivity problem arises because procaspase-3 is present in most cells of the body. However, it has been shown that in many cancers, including certain neuroblastomas, lymphomas, leukemias, melanomas, and liver cancers, procaspase-3 is present in higher concentrations.[1] For instance, lung cancer cells can have over 1000 times more procaspase-3 than normal cells.[1] Therefore, by controlling the dosage, one can achieve selectivity between normal and cancerous cells.

In addition to its stand-alone activity, PAC-1 has also been shown to markedly synergize with a variety of approved cancer drugs, for example with BRAF and MEK inhibitors in mouse models of melanoma,[5] and with conventional chemotherapeutic agents such as doxorubicin in pet dogs with spontaneous cancers including lymphoma and metastatic osteosarcoma,[6] and with temozolomide in pet dogs with naturally occurring glioma.[7]

Vanquish Oncology reported their intention to begin a Phase I human clinical trial in cancer patients to begin in early 2015, and indeed the Phase 1 trial of PAC-1 opened for enrollment in February 2015 (NCT02355535). This trial is being conducted at the University of Illinois Cancer Center in Chicago, at the Sidney Kimmel Cancer Center at Johns Hopkins, and at Regions Hospital in St. Paul, MN. A Phase 1b trial of PAC-1 plus temozolomide opened in late 2017 at the same three sites (NCT03332355); patients with high grade glioma (glioblastoma multiforme (GBM) or anaplastic astrocytoma) after progression following standard first line therapy are eligible for this trial.

Animal trials

PAC-1 is notable for the unique path it has taken to the clinic, as it is possibly the only cancer drug to first be rigorously evaluated in pet dogs with spontaneous cancer as a prelude to the human clinical trial. In 2010, a study showed PAC-1 to be safe for dogs, and a second study published later that same year reported that a PAC-1 derivative (called S-PAC-1) was well tolerated in a small phase I clinical trial of dogs with lymphoma. More recently, in addition to this single-agent activity PAC-1 has shown to potently synergize with approved cancer drugs, for example with doxorubicin in the treatment of pet dogs with lymphoma and metastatic osteosarcoma,[6] and with temozolomide in treating pet dogs with spontaneous glioma.[7]

References

  1. 1 2 3 Putt KS, Chen GW, Pearson JM, Sandhorst JS, Hoagland MS, Kwon JT, Hwang SK, Jin H, Churchwell MI, Cho MH, Doerge DR, Helferich WG, Hergenrother PJ (2006). "Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy l". Nature Chemical Biology. 2 (10): 543–50. doi:10.1038/nchembio814. PMID 16936720.
  2. ↑ Putinski C, Abdul-Ghani M, Stiles R, Brunette S, Dick SA, Fernando P, Megeney LA (2013). "Intrinsic-mediated caspase activation is essential for cardiomyocyte hypertrophy". Proceedings of the National Academy of Sciences. 110 (43): E4079–87. doi:10.1073/pnas.1315587110. PMC 3808644. PMID 24101493.
  3. ↑ Wang F, Wang L, Zhao Y, Li Y, Ping G, Xiao S, Chen K, Zhu W, Gong P, Yang J, Wu C (2014). "A novel small-molecule activator of procaspase-3 induces apoptosis in cancer cells and reduces tumor growth in human breast, liver and gallbladder cancer xenografts". Molecular Oncology. 8 (8): 1640–1652. doi:10.1016/j.molonc.2014.06.015.
  4. ↑ Patel V, Balakrishnan K, Keatin MJ, Wierda WG, Gandhi V (2015). "Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells". Blood. 125 (7): 1126–1136. doi:10.1182/blood-2014-01-546796. PMC 4326772. PMID 25538042.
  5. ↑ Peh J, Fan TM, Wycislo KL, Roth HS, Hergenrother PJ (2016). "The Combination of Vemurafenib and Procaspase-3 Activation is Synergistic in Mutant BRAF Melanomas". Molecular Cancer Therapeutics. 15: 1859–1869. doi:10.1158/1535-7163.MCT-16-0025.
  6. 1 2 Botham RC, Roth HS, Book AP, Roady PJ, Fan TM, Hergenrother, PJ (2016). "Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics". ACS Central Science. 2: 545–559. doi:10.1021/acscentsci.6b00165.
  7. 1 2 Joshi AD, Botham RC, Roth HS, Schlein LJ, Roth HS, Mangraviti A, Borodovsky A, Tyler B, Joslyn S, Looper JS, Podell M, Fan TM, Hergenrother PJ, Riggins GJ (2017). "Synergistic and targeted therapy with a procaspase-3 activator and temozolomide extends survival in glioma rodent models and is feasible for the treatment of canine malignant glioma patients". Oncotarget. 8: 80124–80138. doi:10.18632/oncotarget.19085.

  • Peterson, Q. P.; Goode, D. R.; West, D. C.; Ramsey, K. N.; Lee, J. J.; Hergenrother, P. J. (2009). "PAC-1 Activates Procaspase-3 in vitro Through Relief of Zinc-Mediated Inhibition". J. Mol. Biol. 388 (1): 144–158. doi:10.1016/j.jmb.2009.03.003. PMC 2714579. PMID 19281821.
  • Peterson, Q. P.; Hsu, D. C.; Goode, D. R.; Novotny, C. J.; Totten, R. K. Hergenrother (2009). "Procaspase-3 Activation as an Anti-Cancer Strategy: Structure-Activity Relationship of PAC-1, and its Cellular Co-Localization with Caspase-3". J. Med. Chem. 52 (18): 5721–5731. doi:10.1021/jm900722z. PMC 2749958. PMID 19708658.
  • Lucas, P. W.; Schmit, J. M.; Peterson, Q. P.; West, D. C.; Hsu, D. C.; Novotny, C. J.; Dirikoul, L.; Deorge, D. R.; Garrett, L. D.; et al. (2011). "Pharmacokinetics and Derivation of an Anticancer Dosing Regimen for PAC-1, a Preferential Small Molecule Activator of Procaspase-3, in Healthy Dogs". Invest. New Drugs. 29 (5): 901–911. doi:10.1007/s10637-010-9445-z. PMC 3182491. PMID 20499133.
  • Peterson, Q. P.; Hsu, D. C.; Novotny, C. J.; West, D. C.; Kim, D.; Schmit, J. M.; Dirikolu, L.; Hergenrother, P. J.; Fan, T. M.; et al. (2010). "Discovery and Canine Preclinical Assessment of a Nontoxic Procaspase-3-Activating Compound". Cancer Res. 70 (18): 7232–7241. doi:10.1158/0008-5472.can-10-0766. PMC 3113694. PMID 20823163.
  • West, D. C.; Qin, Y.; Peterson, Q. P.; Thomas, D. L.; Palchaudhuri, R. P.; Morrison, K. C.; Lucas, P. W.; Palmer, A. E.; Fan, T. M.; et al. (2012). "Differential effects of procaspase-3 activating compounds in the induction of cancer cell death". Mol. Pharmaceutics. 9: 1425–1434.
  • Botham, R. C.; Fan, T. M.; Im, I.; Borst, L. B; Dirikolu, L.; Hergenrother, P. J. (2014). "Dual Small-Molecule Targeting of Procaspase-3 Dramatically Enhances Zymogen Activation and Anticancer Activity". J. Am. Chem. Soc. 136 (4): 1312–1319. doi:10.1021/ja4124303. PMC 3954530. PMID 24383395.
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