Delving into the Latest Updates on KDU-731 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CpPI(4)K

Mechanism

CpPI(4)K inhibitors(Cryptosporidium PI4K inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System Disorders

Active Indication

Cryptosporidiosis

Inactive Indication-

Originator Organization

Washington State University

University of Georgia

Novartis AG

Active Organization

Novartis Pharmaceuticals Corp.

University of Georgia

Washington State University

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H16N6O2

InChIKeyYTIYJNWWLQSAAU-UHFFFAOYSA-N

CAS Registry1610610-48-4

With the resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany, of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250 was prioritized for further optimization. The potency of the series lead compound (WEHI-518) was improved 250-fold to low nanomolar levels against parasite blood-stage growth. Parasites selected for resistance to a related compound, MMV396797, were also resistant to WEHI-518 as well as KDU731, an inhibitor of the phosphatidylinositol kinase PfPI4KIIIB, suggesting that this kinase is the target of the pyridyl-furan series. Inhibition of PfPI4KIIIB blocks multiple stages of the parasite's life cycle and other potent inhibitors are currently under preclinical development. MMV396797-resistant parasites possess an E1316D mutation in PfPKI4IIIB that clusters with known resistance mutations of other inhibitors of the kinase. Building upon earlier studies that showed that PfPI4KIIIB inhibitors block the development of the invasive merozoite parasite stage, we show that members of the pyridyl-furan series also block invasion and/or the conversion of merozoites into ring-stage intracellular parasites through inhibition of protein secretion and export into red blood cells.

03 Aug 2018·Expert Review of Anti-infective TherapyQ2 · MEDICINE

Novel treatment strategies and drugs in development for cryptosporidiosis

Q2 · MEDICINE

Review

Author: White, A Clinton ; Chavez, Miguel A

INTRODUCTIONCryptosporidium is a protozoan pathogen that can cause diarrheal disease in healthy and immunosuppressed individuals, worldwide. Recent studies have highlighted the impact of cryptosporidiosis on children in resource-limited countries. Nitazoxanide is the only Food and Drug Administration approved treatment, but it is not consistently effective therapy for cryptosporidiosis in the most vulnerable populations. Areas covered: This review focused on recent published studies evaluating novel drugs and new compounds for the treatment of cryptosporidiosis. Expert commentary: Combinations of approved drugs have demonstrated some activity. Broad screens have demonstrated activity against Cryptosporidium for a number of available drugs, including statins and clofazimine, and the latter has advanced into clinical trials. Cryptosporidium calcium-dependent protein kinase 1 (CDPK1) has been identified as an attractive target for treatment, and bumped kinase inhibitors have been developed which inhibit CDPK1 and are active against Cryptosporidium growth both in vitro and in vivo. Inhibition of Plasmodium lipid kinase PI(4)K8 of Cryptosporidium by KDU731 greatly reduced oocyst shedding and improved diarrhea in calves with limited effects on the human PI(4)K. Another novel potent inhibitor MMV665917 was efficacious in mouse models with cidal activity against Cryptosporidium. Additional compounds have proved active in vitro. So far, only clofazimine has entered human trials.

01 Sep 2017·Trends in ParasitologyQ1 · MEDICINE

New Tools for Cryptosporidium Lead to New Hope for Cryptosporidiosis

Q1 · MEDICINE

Article

Author: Ward, Honorine D

The pyrazolopyridine KDU731 is a promising drug candidate for treatment of diarrhea caused by Cryptosporidium in young children in the resource-limited world. KDU731, a PI (4) kinase inhibitor, blocks Cryptosporidium infection in vitro and in vivo in immunocompromised mice and dramatically reduces oocyst shedding, diarrhea, and dehydration in neonatal calves.

100 Deals associated with KDU-731

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