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Requirements for the Cure of Cancer: Formulating a Plan of Action. Workshop sponsored by the Van Andel Institute Jan. 10-11, 2007. FROM PRINCIPLES TO PRACTICE. SESSION VI(B) The development of technologies for targeting cells that express target patterns Arnold Glazier MD.
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Workshop sponsored by the Van Andel Institute
Jan. 10-11, 2007
The development of technologies for targeting cells that express target patterns
Arnold Glazier MD
Surviving Cell Fraction versus Drug Concentration
Brown JM, Wouters BG.; . Cancer Res. 1999 Apr 1;59(7):1391
Principles that can be applied towards achieving these goals are well known. (Multi-site binding, slow binding, covalent binding, etc..)
The drugs need to be given continuously for prolonged periods of time. (6 months?)
A Minor, Sustained Decrease in the Probability of Cancer Cell Survival can have Profound Effects
Data: Berman JJ, Moore GW; Anal Cell Pathol. 1992 Sep;4(5):359-68
This will achieve Dr. Folkman’s vision by effectively depriving tumor cells of new blood supply, constraining growth and allowing time for the “onion peeling” killing effect to work.
Targeting specificity should be for
Elements of these classes of target patterns are expressed concurrently.
G2/mitotic-specific cyclin-B1 in colon cancer
There is a requirement for approaches that generate a zone of anticancer activity in the local volume that surrounds target patterns
The need for:
Are all the elements of the pattern present ?
Specificity is for the pattern, not the individual elements.
2. Chemical bond formation
3. Breakage of chemical bonds
4. Catalysis of a reaction
5. Dissolution or precipitation
Medicinal Chemistry Boils Down To:
These components exist and are within the scope of current technology.
Ligand Receptor Complex
Ligands are chemical groups that bind together like a lock and key to target receptors.
Kd is in the low nanomolar range.
Tamura S Y., et al., Bioorganic Med Chem Lett,
Chemically altered drug
Triggers are chemical groups then when acted upon by a triggering agent undergo a chemical change.
Enzymes and non-enzymes can serve as triggering agents.
Structural elements that provide the backbone of the drug
Rigidity, multiple sites for linker attachment,
solubility, spatial separation of components,
The male and female parts bind specifically and tightly.
In the ideal case the binding is irreversible.
Molecular clocks provide an adjustable time delay between a triggering event and a chemical change.
Transport into Cell
Intracellular transporter groups can also work by physical, non-receptor mediated mechanisms.
For cell killing both must be present
The cytotoxic agent is toxic only if its target is present
Only cells that have both the target receptor and the triggering
enzyme will be killed.
Binds to GMCSF
Receptor on cells
The drug targets the pattern of urokinase and GMCSF receptor.
Ralph J. Abi-Habib, Shihui Liu, Thomas H. Bugge, Stephen H. Leppla, and Arthur E. Frankel; Blood, 1 October 2004, Vol. 104, No. 7, pp. 2143
The drug is targeted to the microenvironment, released by the triggering enzyme, diffuses to the tumor cell and kills it.
Approaches that produce a zone of toxicity are strongly preferred.
Paired, Independently Targeted
Synergistically Toxic Drugs
No Toxicity Toxicity No Toxicity
Multi-site binding can give an enormous increase in the tightness of binding compared to single site binding
Kd = 10 – 6
Kd = 10 –17
From one receptor create two, from two create four ….
Instead of consuming receptors, the targeted drug will in effect increase the target receptor density.
The more drug that is delivered, the more drug that can be delivered.
Masked Female Adapter
The male and female parts bind with very high affinity.
1.) Component 1 binds to cell receptors.
2.) Triggering enzyme(s) unmask female adapter.
3) Component 2 binds to the unmasked female adaptor.
4) The triggering enzyme unmasks twice as many
new female adaptors.
Repetition of the cycle can deposit a large quantity of drug in a tree like structure
The quantity can increase exponentially
The very binding of a male ligand and female adaptor creates two new female adaptors without the need for a triggering enzyme.
Male and Female
Masked Female Adaptor
Masked Male Adaptor
Female Adaptor from
a second molecule
This can enable the efficient delivery of multiple drugs to each target pattern and prevent the development of drug resistance.
To attract and activate one neutrophil requires only a small number ofchemotactic molecules.
The protease released can also activate MMP-2, MMP-9, and plasminogen.