SHP099 | SHP2 inhibitor

SHP099 (1801747-42-4) is a potent (IC₅₀ = 71 nM) and selective allosteric inhibitor of SHP2.  SHP2 is a non-receptor tyrosine phosphatase that regulates cell survival and proliferation through activating the RAS-ERK pathway. It also mediates programmed cell death 1 (PD-1) and T-lymphocyte attenuator (BTLA) immune checkpoint pathways.  Treatment with SHP099, in combination with ceritinib, halts growth of ALK-inhibitor resistant non-small-cell lung cancer cells.³  Thus, reduction of SHP2 activity is a potential important cancer therapy target.  It showed no activity against a panel of 21 other human phosphatases and 66 kinases. SHP099 has been recently shown to possess significant autophagy inhibition (EC₅₀ = 10.6 µM) activity in a SHP2-independent manner leading to significant anticancer therapeutic efficacies compared to SHP2 specific inhibitors.⁴

References/Citations:

1) Fortanet et al. (2016), Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor; J. Med. Chem., 59 7773
2) Chen et al. (2016), Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases; Nature, 535 148
3) Dardaei et al. (2018), SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors; Nat. Med. 24 512
4) Miao et al. (2024), Off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity in RAS-driven cancers; J. Clin. Invest. 134 e177142