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Development of a Potent Brain-Penetrant EGFR Tyrosine Kinase Inhibitor against Malignant Brain Tumors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-05-01 , DOI: 10.1021/acsmedchemlett.9b00599 Jonathan E Tsang 1 , Lorenz M Urner 1 , Gyudong Kim 1 , Kingsley Chow 1 , Lynn Baufeld 1 , Kym Faull 1 , Timothy F Cloughesy 1 , Peter M Clark 1 , Michael E Jung 1 , David A Nathanson 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-05-01 , DOI: 10.1021/acsmedchemlett.9b00599 Jonathan E Tsang 1 , Lorenz M Urner 1 , Gyudong Kim 1 , Kingsley Chow 1 , Lynn Baufeld 1 , Kym Faull 1 , Timothy F Cloughesy 1 , Peter M Clark 1 , Michael E Jung 1 , David A Nathanson 1
Affiliation
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The epidermal growth factor receptor (EGFR) is genetically altered in nearly 60% of glioblastoma tumors; however, tyrosine kinase inhibitors (TKIs) against EGFR have failed to show efficacy for patients with these lethal brain tumors. This failure is attributed to the inability of clinically tested EGFR TKIs to cross the blood–brain barrier (BBB) and achieve adequate pharmacological levels to inhibit various oncogenic forms of EGFR that drive glioblastoma. Through SAR analysis, we developed compound 5 (JCN037) from an anilinoquinazoline scaffold by ring fusion of the 6,7-dialkoxy groups to reduce the number of rotatable bonds and polar surface area and by introduction of an ortho-fluorine and meta-bromine on the aniline ring for improved potency and BBB penetration. Relative to the conventional EGFR TKIs erlotinib and lapatinib, JCN037 displayed potent activity against EGFR amplified/mutant patient-derived cell cultures, significant BBB penetration (2:1 brain-to-plasma ratio), and superior efficacy in an EGFR-driven orthotopic glioblastoma xenograft model.
中文翻译：
抗恶性脑肿瘤的强效脑渗透性 EGFR 酪氨酸激酶抑制剂的开发
表皮生长因子受体 (EGFR) 在近 60% 的胶质母细胞瘤肿瘤中发生基因改变；然而，针对 EGFR 的酪氨酸激酶抑制剂 (TKI) 未能对患有这些致命性脑肿瘤的患者显示出疗效。这种失败归因于临床测试的 EGFR TKI 无法穿过血脑屏障 (BBB) 并达到足够的药理学水平来抑制驱动胶质母细胞瘤的各种致癌形式的 EGFR。通过 SAR 分析，我们通过 6,7-二烷氧基的环聚以减少可旋转键的数量和极性表面积，并通过引入邻氟和间位，从苯胺基喹唑啉支架开发了化合物5 (JCN037)- 苯胺环上的溴可提高效力和 BBB 渗透。相对于传统的 EGFR TKI 厄洛替尼和拉帕替尼，JCN037 显示出对 EGFR 扩增/突变患者衍生细胞培养物的有效活性、显着的 BBB 渗透（脑血浆比为 2:1）以及在 EGFR 驱动的原位胶质母细胞瘤中的卓越疗效异种移植模型。
更新日期：2020-05-01
中文翻译：
抗恶性脑肿瘤的强效脑渗透性 EGFR 酪氨酸激酶抑制剂的开发
表皮生长因子受体 (EGFR) 在近 60% 的胶质母细胞瘤肿瘤中发生基因改变；然而，针对 EGFR 的酪氨酸激酶抑制剂 (TKI) 未能对患有这些致命性脑肿瘤的患者显示出疗效。这种失败归因于临床测试的 EGFR TKI 无法穿过血脑屏障 (BBB) 并达到足够的药理学水平来抑制驱动胶质母细胞瘤的各种致癌形式的 EGFR。通过 SAR 分析，我们通过 6,7-二烷氧基的环聚以减少可旋转键的数量和极性表面积，并通过引入邻氟和间位，从苯胺基喹唑啉支架开发了化合物5 (JCN037)- 苯胺环上的溴可提高效力和 BBB 渗透。相对于传统的 EGFR TKI 厄洛替尼和拉帕替尼，JCN037 显示出对 EGFR 扩增/突变患者衍生细胞培养物的有效活性、显着的 BBB 渗透（脑血浆比为 2:1）以及在 EGFR 驱动的原位胶质母细胞瘤中的卓越疗效异种移植模型。
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