Agency for Science, Technology and Research

Merck Sharp + Dohme Corp.

Msd International Gmbh (singapore Branch)

Msd International Gmbh

Tsz Ying Yuen

Charles William Johannes

Tomi K Sawyer

David Philip Lane

Nicolas Cedric Boyer

Sookhee Nicole Ha

Gerard Hilinski

Chunhui Huang

Yaw Sing Tan

Greg Verdine

Michael B Garrigou

Pietro Aronica

Srinivasaraghavan Kannan

Anthony W Partridge

Fernando J Ferrer

Christoper J Brown

The invention provides compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein the variables are as described herein. The compounds or their pharmaceutically acceptable salts can inhibit the G12D mutant of Kirsten rat sarcoma (K-Ras) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The invention also provides pharmaceutical compositions which comprise compounds of Formula (I) or pharmaceutically acceptable salts thereof. The invention also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.

Macrocyclic peptides as potent inhibitors of K-RAS G12D mutant

Described herein is an operationally simple, one-pot solid-supported preparation of saturated stapled peptides. Following completion of ruthenium-catalysed metathesis, solid-phase transfer hydrogenation was achieved using triethylhydrosilane at elevated temperatures. The utility of the method has been demonstrated on 14- and 16-mer peptides to yield the corresponding cyclic a-helix stabilised stapled peptides.

Method of preparing stapled peptides

This invention relates to a method for producing an alkenyl 1-aminocyclopropane-1-carboxylic acid of Formula I wherein Ris a protecting group, n is an integer between 1 and 10, and A and B are chiral centres such that when A is S, B is R and when A is R, B is S. The method comprises a stereoselective formation of the cyclopropane moiety by cycloaddition onto a double bond, in a molecule comprising a chiral template, Formula lc. Further provided is the use of Formula I in the production of stapled peptides. 

Building blocks for stapled peptides

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Singapore, Singapore

Tsz Ying Yuen