Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China.
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China.
Eur J Med Chem. 2021 Mar 5;213:113173. doi: 10.1016/j.ejmech.2021.113173. Epub 2021 Jan 18.
Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI-H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFR resistance mutation harboring NCI-H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI-H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFR harboring tumor cell lines (NCI-H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
获得性耐药导致 NSCLC 治疗中 EGFR TKI 的失败。我们设计并合成了一系列新型含羟肟酸的 4-氨基喹唑啉衍生物作为 NSCLC 治疗的不可逆 ErbB/HDAC 多靶点抑制剂，它们在几种 EGFR 野生型癌细胞系（NCI-H838、SK-BR-3、A549、A431）中显示出较弱的抗增殖活性，但对携带 EGFR 耐药突变的 NCI-H1975 细胞仍保持中等活性。机制研究表明，代表性化合物 11e 能够抑制 EGFR 的磷酸化，上调组蛋白 H3 的过度乙酰化，甚至降低 NCI-H1975 细胞中 EGFR 和 Akt 的表达。在进一步的测定中，化合物 11e 还在其他携带 EGFR 的肿瘤细胞系（NCI-H820、Ba/F3_EGFR_Del19-T790M-C797S）中显示出中等的抗增殖活性，在正常细胞系（HL-7702、FHC）中毒性较低。这些设计的多靶点化合物的选择性可以作为一种潜在的策略，避免由于广泛抑制而导致的针对 EGFR 靶向治疗的多种获得性耐药机制，同时避免严重的毒性和副作用。
