Bradshaw J.M.,Principia BioPharma |
McFarland J.M.,Howard Hughes Medical Institute |
Paavilainen V.O.,Howard Hughes Medical Institute |
Bisconte A.,Principia BioPharma |
And 19 more authors.
Nature Chemical Biology | Year: 2015
Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo. © 2015 Nature America, Inc. All rights reserved. Source
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 295.30K | Year: 2014
DESCRIPTION (provided by applicant): We will employ a novel approach to develop unique ALS therapeutics by focusing on drugs that activate a natural cellular protective mechanism, autophagy. Stimulating autophagy is a logical approach to treat the underlying neurodegeneration that causes ALS. It is the prime defense mechanism that neurons have for removing toxic misfolded aggregated proteins, and there is evidence that neurodegeneration of motor neurons (MNs) in ALS is caused by the buildup of toxic, misfolded, aggregated forms of SOD1, TDP43 and FUS. Mutations in these proteins cause familial ALS (fALS), and overexpression or abnormal post-translational modification of these proteins leads to MN degeneration in sporadic ALS (sALS). We will develop drugs that effectively stimulate autophagy in ALS MNs to remove the buildup of toxic proteins to block neurodegeneration and disease progression to treat sALS patients. Our collaborator, Dr. Finkbeiner, previously identified drugs that stimulate autophagy in
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