4YMJ

(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors

4YMJ の概要

• エントリーDOI: 10.2210/pdb4ymj/pdb
• 分子名称: NT-3 growth factor receptor, 4-[6-(benzylamino)imidazo[1,2-b]pyridazin-3-yl]benzonitrile, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: kinase, trk, inhibitor, oncology, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: Q16288
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70693.37

構造登録者

Kreusch, A.,Rucker, P.,Molteni, V.,Loren, J. (登録日: 2015-03-06, 公開日: 2015-06-03, 最終更新日: 2024-11-20)

主引用文献

Choi, H.S.,Rucker, P.V.,Wang, Z.,Fan, Y.,Albaugh, P.,Chopiuk, G.,Gessier, F.,Sun, F.,Adrian, F.,Liu, G.,Hood, T.,Li, N.,Jia, Y.,Che, J.,McCormack, S.,Li, A.,Li, J.,Steffy, A.,Culazzo, A.,Tompkins, C.,Phung, V.,Kreusch, A.,Lu, M.,Hu, B.,Chaudhary, A.,Prashad, M.,Tuntland, T.,Liu, B.,Harris, J.,Seidel, H.M.,Loren, J.,Molteni, V.
(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.
Acs Med.Chem.Lett., 6:562-567, 2015

PubMed Abstract: Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.

PubMed: 26005534
DOI: 10.1021/acsmedchemlett.5b00050

実験手法

X-RAY DIFFRACTION (2 Å)