Working Paper
Authors
- David Quach ,
- Guanghui Tang ,
- Jothi Anantharajan ,
- Nithya Baburajendran ,
- Anders Poulsen ,
- John Wee ,
- Priya Retna ,
- Rong Li ,
- Boping Liu ,
- Doris Tee ,
- Perlyn Kwek ,
- Joma Joy ,
- Wan-Qi Yang ,
- Chong-Jing Zhang ,
- Klement Foo ,
- Thomas Keller ,
- Shao Yao
National University of Singapore
Abstract
Targeted covalent
inhibitors have re-emerged as validated drugs to overcome acquired resistance
in cancer treatment. Herein, by using a carbonyl boronic acid warhead, we
report the structure-based design of BCR-ABL inhibitors via reversible covalent
targeting of the catalytic lysine with improved single-digit nanomolar potency
against both wild-type and mutant ABL kinases, especially ABLT315I
bearing the gatekeeper residue mutation. We show that, by using techniques
including mass spectrometry, time-dependent biochemical assays and X-ray
crystallography, the evolutionarily conserved lysine can be targeted
selectively. Furthermore, we show that the selectivity depends largely on molecular
recognition of the non-covalent pharmacophore in this class of inhibitors,
probably due to the moderate reactivity of the warhead. We report the first
co-crystal structures of covalent inhibitor-ABL kinase domain complexes,
providing insights into the interaction of this warhead with the catalytic
lysine. We also employed label-free mass spectrometry to evaluate potential
off-targets of our compounds at proteome-wide level in different cancer cell
lines.
Content

Supplementary material

David YSQ SI ChemRxiv