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Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

Clayton Hardman1, Stephen Ho1, Akira Shimizu1

  • 1Departments of Chemistry and of Chemical and Systems Biology, Stanford University, Stanford, CA, 94305, USA.

Nature Communications
|April 22, 2020
PubMed

Insights

We designed and synthesized new bryostatin analogs that maintain protein kinase C (PKC) affinity. These analogs show potential for enhancing CAR T/NK cell immunotherapies, particularly for leukemia treatment.

Area of Science:

  • Marine natural products chemistry
  • Medicinal chemistry
  • Immunotherapy

Background:

  • Bryostatin 1, a marine natural product, shows therapeutic potential for HIV/AIDS, neurological disorders, and CAR T/NK cell immunotherapy.
  • Current bryostatin 1 is not optimized for human disease treatment, necessitating the development of improved analogs.

Purpose of the Study:

  • To design, synthesize, and evaluate novel bryostatin 1 analogs.
  • To create analogs that retain affinity for protein kinase C (PKC) while allowing exploration of diverse biological functions.
  • To develop bryostatin analogs for enhanced targeted immunotherapies.

Main Methods:

  • Function-oriented synthesis approach for designing bryostatin analogs.
  • Late-stage diversification strategy to generate a library of analogs.
  • Biological evaluation of analogs for PKC affinity and translocation kinetics.
  • Assessment of analogs for their effect on CD22 cell surface expression.

Main Results:

  • A library of bryostatin analogs was synthesized, retaining affinity for PKC.
  • Analogs exhibited variable protein kinase C (PKC) translocation kinetics.
  • Select analogs significantly increased cell surface expression of CD22.
  • Demonstrated potential of bryostatin analogs in enhancing CAR T cell therapy.

Conclusions:

  • Novel bryostatin analogs were successfully designed and synthesized.
  • These analogs offer a platform for optimizing therapeutic applications by modulating PKC activity.
  • Bryostatin analogs hold significant promise for advancing targeted immunotherapies, especially for leukemias.

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