Hempel Cornelius, Totzke Frank, Schächtele Christoph, Najjar Abdulkarim, Sippl Wolfgang, Ritter Christoph, Hilgeroth Andreas
a Department of Pharmaceutical Chemistry , Institute of Pharmacy, Martin Luther University , Halle , Germany.
b ProQinase GmbH, Freiburg , Germany.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):271-276. doi: 10.1080/14756366.2016.1247062.
Novel 4-benzylamino benzo-anellated pyrrolo[2,3-b]pyridines have been synthesized with varied substitution patterns both at the molecular scaffold of the benzo-anellated ring and at the 4-benzylamino residue. With a structural similarity to substituted thieno[2,3-d]pyrimidines as epidermal growth factor receptor (EGFR) inhibitors, we characterized the inhibition of EGFR for our novel compounds. As receptor heterodimerization gained certain interest as mechanism of cancer cells to become resistant against novel protein kinase inhibitors, we additionally measured the inhibition of insulin-like growth factor receptor IGF-1R which is a prominent receptor for such heterodimerizations with EGFR. Structure-activity relationships are discussed for both kinase inhibitions depending on the varied substitution patterns. We discovered novel dual inhibitors of both receptor tyrosine kinases with interest for further studies to reduce inhibitor resistance developments in cancer treatment.
新型4-苄基氨基苯并稠合吡咯并[2,3 - b]吡啶已被合成，其在苯并稠合环的分子骨架以及4-苄基氨基残基上具有不同的取代模式。由于与作为表皮生长因子受体（EGFR）抑制剂的取代噻吩并[2,3 - d]嘧啶结构相似，我们对新型化合物对EGFR的抑制作用进行了表征。由于受体异二聚化作为癌细胞对新型蛋白激酶抑制剂产生抗性的机制而受到一定关注，我们还测定了胰岛素样生长因子受体IGF-1R的抑制作用，IGF-1R是与EGFR进行此类异二聚化的主要受体。根据不同的取代模式，讨论了两种激酶抑制作用的构效关系。我们发现了两种受体酪氨酸激酶的新型双重抑制剂，有望进一步研究以减少癌症治疗中抑制剂抗性的产生。
