Delving into the Latest Updates on Chlorpromazine/Pentamidine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Pentamidine/chlorpromazine

Target

DRDs x KIF11

Action

antagonists, inhibitors

Mechanism

DRDs antagonists(Dopamine receptors antagonists), KIF11 inhibitors(Kinesin-like protein 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

NeoplasmsSolid tumor

Originator Organization

Zalicus, Inc.

Active Organization-

Inactive Organization

Zalicus, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC17H19ClN2S

InChIKeyZPEIMTDSQAKGNT-UHFFFAOYSA-N

CAS Registry50-53-3

View All Structures (2)

AbstractCombination therapy has proven successful in treating a wide variety of aggressive human cancers. Historically, combination treatments have been discovered through serendipity or lengthy trials using known anticancer agents with similar indications. We have used combination high-throughput screening to discover the unexpected synergistic combination of an antiparasitic agent, pentamidine, and a phenothiazine antipsychotic, chlorpromazine. This combination, CRx-026, inhibits the growth of tumor cell lines in vivo more effectively than either pentamidine or chlorpromazine alone. Here, we report that CRx-026 exerts its antiproliferative effect through synergistic dual mitotic action. Chlorpromazine is a potent and specific inhibitor of the mitotic kinesin KSP/Eg5 and inhibits tumor cell proliferation through mitotic arrest and accumulation of monopolar spindles. Pentamidine treatment results in chromosomal segregation defects and delayed progression through mitosis, consistent with inhibition of the phosphatase of regenerating liver family of phosphatases. We also show that CRx-026 synergizes in vitro and in vivo with the microtubule-binding agents paclitaxel and vinorelbine. These data support a model where dual action of pentamidine and chlorpromazine in mitosis results in synergistic antitumor effects and show the importance of systematic screening for combinations of targeted agents. [Cancer Res 2007;67(23):11359–67]

100 Deals associated with Chlorpromazine/Pentamidine

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