Publications by authors named "Jon K Bowden-Verhoek"

3 Publications

  • Page 1 of 1

Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel reversible Bruton's tyrosine kinase inhibitors.

Bioorg Med Chem 2021 Aug 15;44:116275. Epub 2021 Jun 15.

Sunesis Pharmaceuticals, Inc. 395 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization.
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http://dx.doi.org/10.1016/j.bmc.2021.116275DOI Listing
August 2021

NPT520-34 improves neuropathology and motor deficits in a transgenic mouse model of Parkinson's disease.

Brain 2021 Jun 12. Epub 2021 Jun 12.

Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121 USA.

NPT520-34 is a clinical-stage, small molecule being developed for the treatment of Parkinson's disease and other neurodegenerative disorders. The therapeutic potential of NPT520-34 was first suggested by findings from cell-based assays of alpha-synuclein (ASYN) clearance. As reported here, NPT520-34 was subsequently evaluated for therapeutically relevant actions in a transgenic animal model of Parkinson's disease that overexpresses human ASYN and in an acute lipopolysaccharide (LPS)-challenge model using wild-type mice. Daily administration of NPT520-34 to mThy1-ASYN (Line 61) transgenic mice for one or three months resulted in reduced ASYN pathology, reduced expression of markers of neuroinflammation, and improvements in multiple indices of motor function. In an LPS-challenge model using wild-type mice, a single-dose of NPT520-34 reduced LPS-evoked increases in the expression of several pro-inflammatory cytokines in plasma. These findings demonstrate the beneficial effects of NPT520-34 on both inflammation and protein-pathology endpoints, with consequent improvements in motor function in an animal model of Parkinson's disease. These findings further suggest that NPT520-34 may have two complementary actions: (1) to increase the clearance of neurotoxic protein aggregates and (2) to directly attenuate inflammation. NPT520-34 treatment may thereby address two of the predominate underlying pathophysiological aspects of neurodegenerative disorders such as Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awab214DOI Listing
June 2021

Optimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based screens.

Bioorg Med Chem 2019 07 14;27(13):2905-2913. Epub 2019 May 14.

Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, South San Francisco, CA 94080, United States.

Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton's tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.
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http://dx.doi.org/10.1016/j.bmc.2019.05.021DOI Listing
July 2019
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