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Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
Published on: July 21, 2021
Solution-phase parallel synthesis of Hsp90 inhibitors
Sujin Cho-Schultz1, Monica Jo Patten, Buwen Huang
1Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA.
Journal of Combinatorial Chemistry
|July 9, 2009
Summary
Researchers developed novel orally bioavailable inhibitors targeting heat shock protein 90 (Hsp90) for oncology. Potent analogs were identified, with one showing promising activity and metabolic profile in early studies.
Area of Science:
- Medicinal Chemistry
- Oncology Drug Discovery
- Protein Inhibition
Background:
- Heat shock protein 90 (Hsp90) is a validated target in oncology.
- Development of orally bioavailable Hsp90 inhibitors is crucial for cancer therapy.
Purpose of the Study:
- To discover and synthesize novel, orally bioavailable Hsp90 inhibitors.
- To evaluate the potency and cellular activity of synthesized compounds.
Main Methods:
- Preparation of solution-phase libraries of resorcinol amides and heterocyclic analogs.
- Binding assays and AKT-Luminex cellular assays for activity evaluation.
- Chiral SFC chromatography for enantiomeric resolution.
- Metabolite identification in human hepatocytes.
Main Results:
- 131 racemic resorcinol amide compounds were synthesized and purified.
- Three potent analogs showed functional activity between 0.1 and 0.3 microM.
- Enantiomerically pure compounds (+)-15, (+)-16, and (+)-17 demonstrated IC50 values in the nanomolar range.
- (+)-15 displayed high clearance in hepatocytes, primarily via glucuronidation.
Conclusions:
- Novel Hsp90 inhibitors with oral bioavailability potential were identified.
- Chiral separation and metabolic profiling are key steps in Hsp90 inhibitor development.
- Exploratory libraries incorporating heterocyclic scaffolds show promise for future drug design.
