í í Technology-enabled synthesis of unique building blocks for DNA-encoded libraries Balazs Gyimothy, Krisztián Niesz ComInnex 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 to therapeutic targets, most recently a drug candidate kinase inhibitor. 1-3 DNA-encoded libraries feature: • extreme-large library sizes ( > 10 12 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 generating monoprotected 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 “click” chem. amide coupling Bifunctional BB Examples for ELP Coupling r. Mitsunobu r. Trifunctional BB Examples for ELP Second Boston Symposium of Encoded 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.

Technology-enabled synthesis of unique building blocks for ... · í í Technology-enabled synthesis of unique building blocks for DNA-encoded libraries Balazs Gyimothy, KrisztiánNiesz

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Page 1: Technology-enabled synthesis of unique building blocks for ... · í í Technology-enabled synthesis of unique building blocks for DNA-encoded libraries Balazs Gyimothy, KrisztiánNiesz

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.