Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors.

In order to discovery autotaxin (ATX) and EGFR dual inhibitors with potential therapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC50 values of 18.0 nM and 24.2 nM. Meanwhile, anti-inflammatory assessment against cardiac fibroblasts (CFs) cell and RAW264.7 macrophages led to the discovery of candidate 9a, which exhibited considerable potency both on inhibition rate of 77% towards CFs and on reducing NO production to 1.05 μM at 10 μg/mL. Simultaneously, 9a indicated preferable potency towards ATX with IC50 value of 29.1 nM. Significantly, a RT-PCR study revealed the function of 9a to down-regulate the mRNA expression of TGF-β and TNF-α in a dose-dependent manner. The molecular docking analysis together with the pharmacological studies validated 9a as a potential ATX and EGFR dual inhibitor for IPF-LC treatments.