Discovery of SHP2 Inhibitor GDC-1971 (RLY-1971) Containing a Pyrazolopyrazine Core

Key words

SHP2 inhibitor - GDC-1971 - allosteric inhibitor - solid tumors - clinical candidate - pyrazolopyrazine

Significance

SHP2 is a non-receptor protein tyrosine phosphatase and plays an important role in the regulation of multiple signaling cascades, including RAS/MAPK, PI3K/AKT and JAK/STAT pathways. Due to the genetic alterations, SHP2 has been identified in many human cancers. Significant efforts have therefore been made to identify therapeutic molecules with drug-like property for oral delivery leading to the discovery of allosteric inhibitor, GDC-1971 (RLY-1971). GDC-1971 is currently undergoing clinical evaluation in metastatic solid tumors in combination with divarasib, a KRAS G12C inhibitor.

Comment

The starting point, compound A, was designed by computational methods from the original hit SHP099 (not shown). Based on the analysis of key binding interactions, a pyrazolopyrazine core was designed and found to be moderately active. The strategy for SAR exploration around the pyazolopyrazine core aimed at improving cellular potency, reducing hERG activity, and optimizing half-life. Through the SAR studies, the tetrahydronaphthyridine motif was identified for π-π interaction with Arg111 (B). Further investigation on the H-bonding prone amine moiety led to the spirocyclic derivative C with moderate hERG liability. The addition of an oxygen atom to the spirocyclic amine successfully improved the hERG profile to identify GDC-1971 (RLY-1971). The synthesis of GDC-1971 began with the key intermediate D followed by Pd-catalysed coupling, aromatic substitution, and deprotection.

Publication History

Article published online:
08 December 2023