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Journal article
Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry
Journal of the American Chemical Society, Vol.143(13), pp.4979-4992
07/Apr/2021
PMID: 33761747
Abstract
Targeted covalent inhibitors are an important class of drugs and chemical probes. However, relatively few electrophiles meet the criteria for successful covalent inhibitor design. Here we describe α-substituted methacrylamides as a new class of electrophiles suitable for targeted covalent inhibitors. While typically α-substitutions inactivate acrylamides, we show that hetero α-substituted methacrylamides have higher thiol reactivity and undergo a conjugated addition–elimination reaction ultimately releasing the substituent. Their reactivity toward thiols is tunable and correlates with the pKa/pKb of the leaving group. In the context of the BTK inhibitor ibrutinib, these electrophiles showed lower intrinsic thiol reactivity than the unsubstituted ibrutinib acrylamide. This translated to comparable potency in protein labeling, in vitro kinase assays, and functional cellular assays, with improved selectivity. The conjugate addition–elimination reaction upon covalent binding to their target cysteine allows functionalizing α-substituted methacrylamides as turn-on probes. To demonstrate this, we prepared covalent ligand directed release (CoLDR) turn-on fluorescent probes for BTK, EGFR, and K-RasG12C. We further demonstrate a BTK CoLDR chemiluminescent probe that enabled a high-throughput screen for BTK inhibitors. Altogether we show that α-substituted methacrylamides represent a new and versatile addition to the toolbox of targeted covalent inhibitor design.
Details
- Title
- Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry
- Creators
- Rambabu N. Reddi (null) - 972WIS_INST___97Efrat Resnick (null) - 972WIS_INST___97Adi Rogel (null) - 972WIS_INST___97Boddu Venkateswara Rao (null) - 972WIS_INST___97Ronen Gabizon (null) - 972WIS_INST___97Kim Goldenberg (null) - 972WIS_INST___121Neta Gurwicz (null) - 972WIS_INST___112Daniel Zaidman (null) - 972WIS_INST___97Alexander Plotnikov (null) - 972WIS_INST___890Haim Barr (null) - 972WIS_INST___890Ziv Shulman (null) - 972WIS_INST___121Nir London (Corresponding Author) - 972WIS_INST___97
- Resource Type
- Journal article
- Publication Details
- Journal of the American Chemical Society, Vol.143(13), pp.4979-4992; 07/Apr/2021
- Number of pages
- 14
- Publisher
- American Chemical Society
- Language
- English
- DOI
- https://doi.org/10.1021/jacs.0c10644
- PMID
- 33761747
- Grant note
- We thank Prof. Michael Eck for generously providing the recombinant EGFR kinase domain. N.L. is the Alan and Laraine Fischer Career Development Chair. This research was supported by the Israeli Science Foundation (2462/19), Israeli Ministry of Science and Technology (3-14763), Israel Cancer Research Fund, and the Israel Ministry of Health (3-15102). N.L. is also supported by the Moross Integrated Cancer Center, Rising Tide Foundation, Honey and Dr. Barry Sherman Lab, Dr. Barry Sherman Institute for Medicinal Chemistry, and the estate of Emile Mimran and Nelson P. Sirotsky. R.N.R. was supported by the Rising Tide Foundation.
- Record Identifier
- 993264406103596
Metrics
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