For Clinicians
The science behind CCI-001
A colchicine derivative selective for βIII-tubulin, designed to retain antimitotic activity while reducing the systemic toxicity that has historically limited colchicine in oncology.
Mechanism of action
Tubulin is essential to cell division. βIII-tubulin is the isotype expressed in almost all cancer cells but rarely in healthy tissue (with the exception of brain and testes). CCI-001 targets βIII-tubulin via the colchicine binding site - the site with the greatest sequence diversity across tubulin isotypes - enabling selective disruption of cancer cell mitosis.
Colchicine itself is a well-characterized microtubule-disrupting alkaloid, but its systemic toxicity has prevented its use in oncology. PharmaMatrix has engineered novel colchicine derivatives that retain potent antimitotic activity while substantially reducing off-target effects and avoiding blood-brain barrier penetration.
Preclinical results
- Binds at the optimal site to inhibit βIII-tubulin function and arrest tumor growth.
- More potent against bladder cancer in cell-based assays than several licensed agents.
- Enhances tumor sensitivity vs. other tubulin inhibitors.
- Fewer off-target effects than other tubulin inhibitors.
- Emerging activity against breast cancer and potential utility in other indications.
The testing cascade
- In silico screening of candidate compounds.
- In vitro binding assays against tumor target proteins.
- Inhibition of cancer (and normal) cell growth in culture.
- Tumor growth studies in animal models.
- Pharmacokinetics - minimizing brain penetration, organ protection.
- GLP/GMP/IND-enabling studies.
- Regulatory approval for clinical trials.
Treatment pathway
Instead of allowing tumors to proliferate, CCI-001 binds at the source of βIII-tubulin expression, halts mitotic spindle formation, prevents sister cell division, and ultimately destroys the tumor at its root through programmed cell death.
Selected publications
Peer-reviewed work from the Tuszynski group on colchicine derivatives.
- L. Johnson, I.S. Goping, A. Rieger, J. Mane, T. Huzil, A. Banerjee, R.F. Luduena, B. Hssani, P. Winter, J.A. Tuszynski. Novel Colchicine Derivatives and Their Anti-Cancer Activity. Current Topics in Medicinal Chemistry, 17(22):2538-2558 (2016).
- Mane JY, Semenchenko V, Perez-Pineiro R, Winter P, Wishart D, Tuszynski JA. Experimental and computational study of the interaction of novel colchicinoids with a recombinant human αI/βI-tubulin heterodimer. Chem Biol Drug Des 82:60–70 (2013).
- Ashrafuzzaman M, Tseng CY, Duszyk M, Tuszynski JA. Chemotherapy drugs form ion pores in membranes due to physical interactions with lipids. Chem Biol Drug Des 80:992–1002 (2012).
- Huzil JT, Mane J, Tuszynski JA. Computer assisted design of second-generation colchicine derivatives. Interdiscip Sci Comput Life Sci 2:169–174 (2010).
- Huzil JT, Winter P, Johnson L, Weis AL, Bakos T, Banerjee A, Luduena RF, Damaraju S, Tuszynski JA. Computational design and biological testing of highly cytotoxic colchicine ring A modifications. Chem Biol Drug Des 75:541–550 (2010).
- Tseng CY, Mane JY, Winter P, Johnson L, Huzil T, Izbicka E, Luduena RF, Tuszynski JA. Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives. Mol Cancer 9:131 (2010).
- Bartusik D, Tomanek B, Lattová E, Perreault H, Tuszynski J, Fallone G. Derivatives of thiocolchicine and its applications to CEM cells treatment using 19F magnetic resonance ex vivo. Bioorg Chem 38:1–6 (2010).
- Bartusik D, Tomanek B, Lattová E, Perreault H, Tuszynski J, Fallone G. The efficacy of new colchicine derivatives and viability of the T-Lymphoblastoid cells in three-dimensional culture using 19F MRI and HPLC-UV ex vivo. Bioorganic Chemistry 37:193–201 (2009).
- Huzil JT, Barakat K, Tuszynski JA. Electrostatic contributions to colchicine binding within tubulin isotypes. Electromagn Biol Med 28:355–364 (2009).
- Mane JY, Klobukowski M, Huzil JT, Tuszynski J. Free energy calculations on the binding of colchicine and derivatives with α/β-tubulin isoforms. J Chem Inf Model 48:1824–1832 (2008).
Patent: J.A. Tuszynski, "Novel Colchicine Derivatives, Methods and Uses Thereof", International PCT Patent Application No. PCT/CA2010/001199, Sim & McBurney, Toronto, filed July 30, 2010. Allowed by USPTO June 1, 2016; by the Canadian Intellectual Property Office October 18, 2017; by the EPO December 4, 2017.
Clinician inquiries
Investigators, oncology centers, and collaborators - request the full clinical brief.