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(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.

Choi HS, Rucker PV, 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 HM, Loren J, Molteni V
ACS Med Chem Lett 6 562-7 (2015)
Related entries: 4ymj, 4yps

Cited: 16 times
EuropePMC logo PMID: 26005534

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.

Reviews - 4yne mentioned but not cited (1)

  1. Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers. Jiang T, Wang G, Liu Y, Feng L, Wang M, Liu J, Chen Y, Chen Y, Ouyang L. Acta Pharm Sin B 11 355-372 (2021)

Articles - 4yne mentioned but not cited (3)

  1. Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application. Yan W, Lakkaniga NR, Carlomagno F, Santoro M, McDonald NQ, Lv F, Gunaganti N, Frett B, Li HY. J Med Chem 62 1731-1760 (2019)
  2. Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations. Murray BW, Rogers E, Zhai D, Deng W, Chen X, Sprengeler PA, Zhang X, Graber A, Reich SH, Stopatschinskaja S, Solomon B, Besse B, Drilon A. Mol Cancer Ther 20 2446-2456 (2021)
  3. TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors. Cocco E, Lee JE, Kannan S, Schram AM, Won HH, Shifman S, Kulick A, Baldino L, Toska E, Arruabarrena-Aristorena A, Kittane S, Wu F, Cai Y, Arena S, Mussolin B, Kannan R, Vasan N, Gorelick AN, Berger MF, Novoplansky O, Jagadeeshan S, Liao Y, Rix U, Misale S, Taylor BS, Bardelli A, Hechtman JF, Hyman DM, Elkabets M, de Stanchina E, Verma CS, Ventura A, Drilon A, Scaltriti M. Cancer Discov 11 126-141 (2021)


Reviews citing this publication (6)

  1. Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II. Bailey JJ, Schirrmacher R, Farrell K, Bernard-Gauthier V. Expert Opin Ther Pat 27 831-849 (2017)
  2. Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I. Bailey JJ, Schirrmacher R, Farrell K, Bernard-Gauthier V. Expert Opin Ther Pat 27 733-751 (2017)
  3. Recent Advances in PROTACs for Drug Targeted Protein Research. Yao T, Xiao H, Wang H, Xu X. Int J Mol Sci 23 10328 (2022)
  4. Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling. Zhang H, He F, Gao G, Lu S, Wei Q, Hu H, Wu Z, Fang M, Wang X. Molecules 28 943 (2023)
  5. Recent advancements in targeted protein knockdown technologies-emerging paradigms for targeted therapy. Joshi M, Dey P, De A. Explor Target Antitumor Ther 4 1227-1248 (2023)
  6. Small Molecule Inhibitors as Therapeutic Agents Targeting Oncogenic Fusion Proteins: Current Status and Clinical. Kong Y, Jiang C, Wei G, Sun K, Wang R, Qiu T. Molecules 28 4672 (2023)

Articles citing this publication (6)

  1. Predictive Model for Site-Selective Aryl and Heteroaryl C-H Functionalization via Organic Photoredox Catalysis. Margrey KA, McManus JB, Bonazzi S, Zecri F, Nicewicz DA. J Am Chem Soc 139 11288-11299 (2017)
  2. Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival. Jawhari S, Bessette B, Hombourger S, Durand K, Lacroix A, Labrousse F, Jauberteau MO, Ratinaud MH, Verdier M. Carcinogenesis 38 592-603 (2017)
  3. Structural characterization of nonactive site, TrkA-selective kinase inhibitors. Su HP, Rickert K, Burlein C, Narayan K, Bukhtiyarova M, Hurzy DM, Stump CA, Zhang X, Reid J, Krasowska-Zoladek A, Tummala S, Shipman JM, Kornienko M, Lemaire PA, Krosky D, Heller A, Achab A, Chamberlin C, Saradjian P, Sauvagnat B, Yang X, Ziebell MR, Nickbarg E, Sanders JM, Bilodeau MT, Carroll SS, Lumb KJ, Soisson SM, Henze DA, Cooke AJ. Proc Natl Acad Sci U S A 114 E297-E306 (2017)
  4. Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32. Sharma RK, Singh M, Ghimeray K, Juneja P, Dev G, Pulavarthi S, Reddy SR, Akundi RS. Molecules 26 5319 (2021)
  5. LY294002 induces in vitro apoptosis and overexpression of p75NTR in human uterine leiomyosarcoma HTB 114 cells. Pistilli A, Rende M, Crispoltoni L, Montagnoli C, Stabile AM. Growth Factors 33 376-383 (2015)
  6. Research Progress on Small Molecules Inhibitors Targeting TRK Kinases. Liu J, Zhang Y, Zhu Y, Tian L, Tang M, Shen J, Chen Y, Ding S. Curr Med Chem 30 1175-1192 (2023)


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