technology-enabled synthesis of unique building blocks for ... · í í technology-enabled...
Post on 08-May-2020
14 Views
Preview:
TRANSCRIPT
í
í
Technology-enabled synthesis of unique building blocks for DNA-encoded librariesBalazs Gyimothy, Krisztián NieszComInnex Inc., Zahony u. 7., 1031 Budapest, Hungary
Background:
Selection-based screening of large DNA-encoded libraries (DELs) of lead-like molecules is now a validated method to identify bioactive compounds that has already led to many identified hits totherapeutic targets, most recently a drug candidate kinase inhibitor.1-3
DNA-encoded libraries feature:
• extreme-large library sizes ( > 1012 compounds),
• simpler storage (single test tube),
• easier & cost effective maintenance and usage,
• but DNA-compatible chemistry must by applied!
Technology-enabled molecules provide:
• Low aromaticity
• High 3D character (fsp3)
• Improved physicochemical and ADMET properties (logP, logD, solubility, etc.)
• Functional groups accessible towards further chemistry
Novel Building Blocks (BBs) ready for synthesis:
• Transition of know-how from the high fsp3“fragment” space towards generatingmonoprotected bi- and trifunctional BBs for ELP.
Reduction rules collected, stored and applied during structure design and validation steps
✓ Reactivity✓ Stereoselectivity✓ Regioselectivity
Know-how
Examples for technology-assisted synthesis of trifunctional DEL Building Blocks
Olefin metathesis
Phoenix Flow reactor
Trifunctional BB
Trifunctional BB
Trifunctional BB
Selective ring saturation
H-Cube Pro
Ring closure
Phoenix Flow Reactor
“clic
k” c
he
m.
amid
eco
up
ling
Bifunctional BB Examples for ELP
Co
up
ling
r.M
itsu
no
bu
r.
Trifunctional BB Examples for ELP
Second Boston Symposium ofEncoded Library Platforms (BSELP)04 August 2017, Walthalm, MA, USA
Future perspectives:
• Setting up an open collaboration with partners
• Expanding chemistry space by the means of flow technology
References:
1.) Goodnow, R. A. J. et al., Nat. Rev. Drug. Discov., 16, 2017, 131.
2.) Harris, P. A. et al., J. Med. Chem., 59, 2016, 2163.
3.) Lazaar, A. L. et al., Br. J. Clin. Pharmacol., 81, 2016, 971.
top related