Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Singh, Baljinder; Sharma, Amrita; Gutta, Naresh; Rivers, Mitch; Gadekar, Pradip K.; Greene, Brady; Chichioco, Michael; Sanz-Rodriguez, Carlos E.; Fu, Courtney; Leblanc, Catherine; Burchfield, Erin; Sharif, Nyle; Hoffman, Benjamin U.; Kumar, Gaurav; Purmal, Andrei A.; Mensa-Wilmot, Kojo; Pollastri, Michael P.

doi:10.1021/acs.jmedchem.2c01767

Cited by 5 publications

(2 citation statements)

References 19 publications

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“…Two compounds from this series have previously been advanced into PK studies and 8c was found to have excellent exposure in the brain and, at 40 mg/kg per os (P.O. ; oral administration), it had a brain:blood ratio at 1 h of 5.1 (male) and 4.1 (female); and at 4 h it was 3.6 (male) and 5.2 (female; Singh et al, 2023 ). Further SAR scoping with a focus on reducing the lipophilicity and maintaining the potency is underway.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

Ferrins,

Buskes,

Kapteyn

et al. 2023

Front. Microbiol.

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Acanthamoeba species, Naegleria fowleri, and Balamuthia mandrillaris are opportunistic pathogens that cause a range of brain, skin, eye, and disseminated diseases in humans and animals. These pathogenic free-living amoebae (pFLA) are commonly misdiagnosed and have sub-optimal treatment regimens which contribute to the extremely high mortality rates (>90%) when they infect the central nervous system. To address the unmet medical need for effective therapeutics, we screened kinase inhibitor chemotypes against three pFLA using phenotypic drug assays involving CellTiter-Glo 2.0. Herein, we report the activity of the compounds against the trophozoite stage of each of the three amoebae, ranging from nanomolar to low micromolar potency. The most potent compounds that were identified from this screening effort were: 2d (A. castellanii EC50: 0.92 ± 0.3 μM; and N. fowleri EC50: 0.43 ± 0.13 μM), 1c and 2b (N. fowleri EC50s: <0.63 μM, and 0.3 ± 0.21 μM), and 4b and 7b (B. mandrillaris EC50s: 1.0 ± 0.12 μM, and 1.4 ± 0.17 μM, respectively). With several of these pharmacophores already possessing blood–brain barrier (BBB) permeability properties, or are predicted to penetrate the BBB, these hits present novel starting points for optimization as future treatments for pFLA-caused diseases.

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Section: Resultsmentioning

confidence: 99%

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

Ferrins,

Buskes,

Kapteyn

et al. 2023

Front. Microbiol.

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“…Indeed, recent studies have reported encouraging results for the use of CBL137 as a potential latency-reversing agent in HIV-1 infection, and even as a lead for drug discovery efforts against human African trypanosomiasis, further underscoring the potential of CBL137 as a therapeutic against various infectious diseases. 76,77…”

Section: Discussionmentioning

confidence: 99%

A nucleosome switch primes Hepatitis B Virus infection

Prescott

Mansisidor

Bram

et al. 2023

Preprint

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Chronic hepatitis B virus (HBV) infection is an incurable global health threat responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The first viral protein expressed, HBx, induces degradation of a host silencing factor to facilitate infection. However, the relationship between cccDNA chromatin and early HBx transcription remains poorly understood. Establishing reconstituted viral minichromosomes, we found that nucleosomes in cccDNA drive HBx transcription. We corroborated these findings in cells and further showed that the chromatin destabilizing drug CBL137 inhibits infection in hepatocytes. Our results shed new light on a long-standing paradox and represent a novel therapeutic avenue for the treatment of chronic HBV.One-Sentence SummaryChromatin assembly on the Hepatitis B Virus genome drives transcription of the critical viral oncogene HBx, and thus infection.

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Discovery of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide as dual CSF-1R/c-Kit Inhibitors with improved stability and BBB permeability

Baek,

Kim,

Jun

et al. 2024

European Journal of Medicinal Chemistry

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Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Cited by 5 publications

References 19 publications

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

A nucleosome switch primes Hepatitis B Virus infection

Discovery of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide as dual CSF-1R/c-Kit Inhibitors with improved stability and BBB permeability

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