A phase I double-blind, placebo controlled (part B only), randomised trial to evaluate the safety, tolerability and pharmacokinetics of single dose in fed state, and repeated doses of DNDI-6899 in healthy participants.

Start Date30 Sep 2024

Sponsor / Collaborator

Drugs for Neglected Diseases initiative

NCT03874234 / TerminatedPhase 1

A Randomized, Double-blind (Sponsor Unblinded), Placebo-controlled, First Time in Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single (in Both Fed and Fasted States) and Repeat Doses of GSK3186899 in Healthy Participants

The purpose of this study is to evaluate the safety, tolerability and PK profile of single and repeat ascending doses of GSK3186899 in healthy subjects. This is a Phase 1 first time in human study, to investigate the effect of food on PK of GSK3186899. This study will consists of two parts. Part A (dose escalation phase) will be a single ascending, sequential cross-over design in cohorts 1, 2 and 3 of subjects. Cohort 1 and 2 will be 4-way cross-over which includes 4 dosing regimens of GSK3186899 and placebo (3:1 ratio) under fasted conditions. Cohort 3 will be 2-way cross-over which includes 2 treatment periods, 2 dosing regimens in fasted and fed conditions. In Part B (repeat dose escalation phase) subjects will be randomized to receive repeat doses of either GSK3186899 or placebo (3:1 ratio) in either fed or fasted conditions. Part B will be conducted based on the review of all safety, tolerability and PK data from Part A. The study duration includes screening, treatment periods and follow-up.

Start Date30 Apr 2019

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with GSK-3186899

100 Translational Medicine associated with GSK-3186899

100 Patents (Medical) associated with GSK-3186899

Literatures (Medical) associated with GSK-3186899

14 Feb 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

Q1 · MEDICINE

Article

Author: Martin, Franck ; Daugan, Alain ; Gresham, Stephanie L. ; Reid, Iain H. ; Albrecht, Sébastian ; Read, Kevin D. ; Ajakane, Myriam ; Cleghorn, Laura A.T. ; Pena, Imanol ; De Rycker, Manu ; Ghidelli-Disse, Sonja ; Manthri, Sujatha ; Hindley, Sean J. ; Smith, Alasdair ; Norval, Suzanne ; Ruiz-Gomez, Jose Ramon ; Campbell, Lorna ; Cantizani-Perez, Juan ; Boesche, Markus ; Simeons, Frederick R.C. ; Brand, Stephen ; Smith, Victoria C. ; Álvarez-Pedraglio, Ana Isabel ; Hill, Alan P. ; Quesada-Campos, Maria Teresa ; Gonzalez, Silvia ; Riley, Jennifer ; Stojanovski, Laste ; Nguyen, Van Loc ; Fiandor, Jose M. ; Shishikura, Yoko ; Copley, Royston C.B. ; Revill, Charlotte ; Lowe, Rhiannon M. ; Gray, David W. ; Thompson, Stephen ; Patterson, Stephen ; Thomas, John ; Underwood, Tim ; Ferrer, Santiago ; Thomas, Michael G. ; Osuna-Cabello, Maria ; MacKenzie, Claire J. ; Gilbert, Ian H. ; MacLean, Lorna ; Woodland, Andrew ; Spinks, Daniel ; Wyatt, Paul G. ; Crouch, Sabrinia D. ; Miles, Timothy J. ; Drewes, Gerard ; Miguel-Siles, Juan

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

09 Aug 2018·NatureQ1 · CROSS-FIELD

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Q1 · CROSS-FIELD

Article

Author: Ferguson, Michael A J ; Sastry, Lalitha ; Fiandor, Jose M ; Read, Kevin D ; Fairlamb, Alan H ; Lowe, Rhiannon ; Drewes, Gerard ; Gilbert, Ian H ; Gresham, Stephanie ; MacLean, Lorna M ; Thomas, Michael ; Albrecht, Sebastian ; Simeons, Frederick R C ; Boesche, Markus ; Berriman, Matt ; Pflaumer, Hannah ; Urbaniak, Michael D ; Dixon, Susan ; Crouch, Sabrinia ; De Rycker, Manu ; Stojanovski, Laste ; Wyatt, Paul G ; Connolly, Paul ; Ghidelli-Disse, Sonja ; Manthri, Sujatha ; Gray, David W ; Zuccotto, Fabio ; Homeyer, Nadine ; Miles, Timothy J ; Wyllie, Susan ; Patterson, Stephen ; Otto, Thomas D

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.

BiomoleculesQ3 · BIOLOGY

A Molecular Modeling Approach to Identify Potential Antileishmanial Compounds Against the Cell Division Cycle (cdc)-2-Related Kinase 12 (CRK12) Receptor of Leishmania donovani

Q3 · BIOLOGY

ArticleOA

Author: Asiedu, Seth O. ; Miller, Whelton A. ; Kwofie, Samuel K. ; Broni, Emmanuel ; Wilson, Michael D.

The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania is well known. This illness was included in the list of neglected tropical diseases targeted for elimination by the World Health Organization. However, the increasing evidence of resistance to existing antimonial drugs has made the eradication of the disease difficult to achieve, thus warranting the search for new drug targets. We report here studies that used computational methods to identify inhibitors of receptors from natural products. The cell division cycle-2-related kinase 12 (CRK12) receptor is a plausible drug target against Leishmania donovani. This study modelled the 3D molecular structure of the L. donovani CRK12 (LdCRK12) and screened for small molecules with potential inhibitory activity from African flora. An integrated library of 7722 African natural product-derived compounds and known inhibitors were screened against the LdCRK12 using AutoDock Vina after performing energy minimization with GROMACS 2018. Four natural products, namely sesamin (NANPDB1649), methyl ellagic acid (NANPDB1406), stylopine (NANPDB2581), and sennecicannabine (NANPDB6446) were found to be potential LdCRK12 inhibitory molecules. The molecular docking studies revealed two compounds NANPDB1406 and NANPDB2581 with binding affinities of −9.5 and −9.2 kcal/mol, respectively, against LdCRK12 which were higher than those of the known inhibitors and drugs, including GSK3186899, amphotericin B, miltefosine, and paromomycin. All the four compounds were predicted to have inhibitory constant (Ki) values ranging from 0.108 to 0.587 μM. NANPDB2581, NANPDB1649 and NANPDB1406 were also predicted as antileishmanial with Pa and Pi values of 0.415 and 0.043, 0.391 and 0.052, and 0.351 and 0.071, respectively. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations reinforced their good binding mechanisms. Most compounds were observed to bind in the ATP binding pocket of the kinase domain. Lys488 was predicted as a key residue critical for ligand binding in the ATP binding pocket of the LdCRK12. The molecules were pharmacologically profiled as druglike with inconsequential toxicity. The identified molecules have scaffolds that could form the backbone for fragment-based drug design of novel leishmanicides but warrant further studies to evaluate their therapeutic potential.

100 Deals associated with GSK-3186899

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Indication	Highest Phase	Country/Location	Organization	Date
Leishmaniasis	Phase 1	-	University Of Dundee	-

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