21 research outputs found
Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis
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
Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis
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
(<b>1</b>) for VL
Deep into the mud: ecological and socio-economic impacts of the dam breach in Mariana, Brazil.
Made available in DSpace on 2018-08-03T00:56:13Z (GMT). No. of bitstreams: 1
1s2.0S1679007316301104main.pdf: 3842180 bytes, checksum: 114f6d73ea48a614146a9f67588338ad (MD5)
Previous issue date: 2017-02-06bitstream/item/180810/1/1-s2.0-S1679007316301104-main.pd
Author Correction:Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis (Nature, (2018), 560, 7717, (192-197), 10.1038/s41586-018-0356-z)
Jacobian matrix for near-infrared remote sensing based on vector radiative transfer model
Biochemical Screening of Five Protein Kinases from <i>Plasmodium falciparum</i> against 14,000 Cell-Active Compounds
<div><p>In 2010 the identities of thousands of anti-<i>Plasmodium</i> compounds were released publicly to facilitate malaria drug development. Understanding these compoundsâ mechanisms of actionâi.e., the specific molecular targets by which they kill the parasiteâwould further facilitate the drug development process. Given that kinases are promising anti-malaria targets, we screened ~14,000 cell-active compounds for activity against five different protein kinases. Collections of cell-active compounds from GlaxoSmithKline (the ~13,000-compound Tres Cantos Antimalarial Set, or TCAMS), St. Jude Childrenâs Research Hospital (260 compounds), and the Medicines for Malaria Venture (the 400-compound Malaria Box) were screened in biochemical assays of <i>Plasmodium falciparum</i> calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4), mitogen-associated protein kinase 2 (MAPK2/MAP2), protein kinase 6 (PK6), and protein kinase 7 (PK7). Novel potent inhibitors (IC<sub>50</sub> < 1 ÎŒM) were discovered for three of the kinases: CDPK1, CDPK4, and PK6. The PK6 inhibitors are the most potent yet discovered for this enzyme and deserve further scrutiny. Additionally, kinome-wide competition assays revealed a compound that inhibits CDPK4 with few effects on ~150 human kinases, and several related compounds that inhibit CDPK1 and CDPK4 yet have limited cytotoxicity to human (HepG2) cells. Our data suggest that inhibiting multiple <i>Plasmodium</i> kinase targets without harming human cells is challenging but feasible.</p></div