Synthesis and biological evaluation of morpholine-substituted diphenylpyrimidine derivatives (Mor-DPPYs) as potent EGFR T790M inhibitors with improved activity toward the gefitinib-resistant non-small cell lung cancers (NSCLC).

Potential new EGFRT790M inhibitors comprised of structurally modified diphenylpyrimidine derivatives bearing a morpholine functionality (Mor-DPPYs) were used to improve the activity and selectivity of gefitinib-resistant non-small cell lung cancer (NSCLC) treatment. This led to the identification of inhibitor 10c, which displayed high activity against EGFRT790M/L858R kinase (IC50 = 0.71 nM) and repressed H1975 cell replication harboring EGFRT790M mutations at a concentration of 0.037 μM. Inhibitor 10c demonstrated high selectivity (SI = 631.9) for T790M-containing EGFR mutants over wild type EGFR, suggesting that it will cause less side effects. Moreover, this compound also shows promising antitumor efficacy in a murine EGFRT790M/L858R-driven H1975 xenograft model without affecting body weight. This study provides new potential lead compounds for further development of anti-NSCLC drugs.

Song Z ，Huang S ，Yu H ，Jiang Y ，Wang C ，Meng Q ，Shu X ，Sun H ，Liu K ，Li Y ，Ma X ... -  《-》

TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells.

Otani H ，Yamamoto H ，Takaoka M ，Sakaguchi M ，Soh J ，Jida M ，Ueno T ，Kubo T ，Asano H ，Tsukuda K ，Kiura K ，Hatakeyama S ，Kawahara E ，Naomoto Y ，Miyoshi S ，Toyooka S ... -  《PLoS One》

Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.

Hu P ，Han DX ，Ruan RS ，Zheng LM ，Chou SH ，Tzeng CM ... -  《Oncotarget》

C-2 (E)-4-(Styryl)aniline substituted diphenylpyrimidine derivatives (Sty-DPPYs) as specific kinase inhibitors targeting clinical resistance related EGFR(T790M) mutant.

With the aim to overcome the drug resistance induced by the EGFR T790M mutation (EGFRT790M), herein, a family of diphenylpyrimidine derivatives (Sty-DPPYs) bearing a C-2 (E)-4-(styryl)aniline functionality were designed and synthesized as potential EGFRT790M inhibitors. Among them, the compound 10e displayed strong potency against the EGFRT790M enzyme, with the IC50 of 11.0nM. Compound 10e also showed a higher SI value (SI=49.0) than rociletinib (SI=21.4), indicating its less side effect. In addition, compound 10e could effectively inhibit the proliferation of H1975 cells harboring the EGFRT790M mutation, within the concentration of 2.91μM. Significantly, compound 10e has low toxicity against the normal HBE cell (IC50=22.48μM). This work provided new insights into the discovery of potent and selective inhibitor against EGFRT790M over wild-type (EGFRWT).

Song A ，Zhang J ，Ge Y ，Wang C ，Meng Q ，Tang Z ，Peng J ，Liu K ，Li Y ，Ma X ... -  《-》

Structural optimization of diphenylpyrimidine scaffold as potent and selective epidermal growth factor receptor inhibitors against L858R/T790M resistance mutation in nonsmall cell lung cancer.

A new class of thiodiphenylpyrimidine analogs (Thio-DPPY) were synthesized as potent and selective EGFR T790M inhibitors to overcome gefitinib resistance in nonsmall cell lung cancer (NSCLC). This structural optimization led to the identification of two potent EGFRT790M/L858R inhibitors, 14a and 14e, which possess IC50 values of 27.5 and 9.1 nM, respectively. Moreover, compounds 14a (SI > 36.4) and 14e (SI > 109.9) exhibited high selectivity and low activity against the wild-type EGFR (IC50  > 1,000 nM). In particular, compound 14a also displayed strong potency against EGFRT790M -mutated H1975 cells (IC50  = 0.074 μM), but weak activity toward normal cells HBE (IC50  > 40 μM) and LO-2 (IC50  = 9.891 μM). It is important that compound 14a (SI = 52.6) significantly improved the selectivity against mutant H1975 cells over wild-type A431 cells than rociletinib (SI = 6.0), thus revealing its slight cell cytotoxicity. This study provides a promising Thio-DPPY derivative as enhanced EGFR T790M inhibitor, and also revealed valuable clues for further optimization of DPPY scaffold to overcome NSCLC resistance.

Yi Y ，Wang L ，Zhao D ，Huang S ，Wang C ，Liu Z ，Sun H ，Liu K ，Ma X ，Li Y ... -  《-》