4YMJ

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

Summary for 4YMJ

• Entry DOI: 10.2210/pdb4ymj/pdb
• Descriptor: NT-3 growth factor receptor, 4-[6-(benzylamino)imidazo[1,2-b]pyridazin-3-yl]benzonitrile, GLYCEROL, ... (5 entities in total)
• Functional Keywords: kinase, trk, inhibitor, oncology, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: Q16288
• Total number of polymer chains: 2
• Total formula weight: 70693.37

Authors

Kreusch, A.,Rucker, P.,Molteni, V.,Loren, J. (deposition date: 2015-03-06, release date: 2015-06-03, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)