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. 2015 Mar 16;6(5):562-7.
doi: 10.1021/acsmedchemlett.5b00050. eCollection 2015 May 14.

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

Ha-Soon Choi  1 , Paul V Rucker  1 , Zhicheng Wang  1 , Yi Fan  1 , Pamela Albaugh  1 , Greg Chopiuk  1 , Francois Gessier  1 , Fangxian Sun  1 , Francisco Adrian  1 , Guoxun Liu  1 , Tami Hood  1 , Nanxin Li  1 , Yong Jia  1 , Jianwei Che  1 , Susan McCormack  1 , Allen Li  1 , Jie Li  1 , Auzon Steffy  1 , AnneMarie Culazzo  1 , Celine Tompkins  1 , Van Phung  1 , Andreas Kreusch  1 , Min Lu  1 , Bin Hu  1 , Apurva Chaudhary  1 , Mahavir Prashad  1 , Tove Tuntland  1 , Bo Liu  1 , Jennifer Harris  1 , H Martin Seidel  1 , Jon Loren  1 , Valentina Molteni  1
Affiliations

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

Ha-Soon Choi et al. ACS Med Chem Lett. .

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.

Keywords: (R)-2-phenylpyrrolidine; GNF-8625; Neurotrophins; TRK; imidazopyridazines; tropomyosin receptor kinase.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
X-ray cocrystal structure of 1 (carbon in yellow) binding to the active site of TRKC kinase. Hydrogen bonds are depicted as dashed lines. Nitrogen atoms are shown in blue, oxygen atoms in red, and a water molecule depicted as a red sphere.
Figure 2
Figure 2
X-ray cocrystal structure of TRKA with 10. The fluorophenyl points toward the pocket usually occupied by the ribose from ATP. The protein adopts a DFG-in conformation to allow for the fluorophenyl to bind. Although the 10 racemate was used for crystallization, only the R-enantiomer binds to TRKA. Color coding according to Figure 1.
Scheme 1
Scheme 1. Imidazopyridazines SAR Progression and Numbering Assignment
Figure 3
Figure 3
X-ray cocrystal structure of TRKA with the R-enantiomer of 14. The protein adopts the DFG-in conformation. Compound 14 maintains the key hydrogen bond between the hinge NH of Met592 and N1 of imidazopyridazine. Surprisingly, the imidazopyridazine is now flipped. This allows for the fluorophenyl group to better fit the ribose binding pocket compared to 10. Color coding according to Figure 1.
Figure 4
Figure 4
KM12 efficacy model in female CRL RNU nude rats with compound 17 (GNF-8625). Animals were transplanted with KM12 tumor tissues, and dosing began 10 days postimplant. Vehicle and 17 were dosed twice a day (bid) for 14 days. Efficacy measured as tumor volume.
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References

    1. Huang E. J.; Reichardt L. F. TRK Receptors: Roles in Neuronal Signal Transduction. Annu. Rev. Biochem. 2003, 72, 609–642. - PubMed
    1. Pierotti M. A.; Greco A. Oncogenic Rearrangements of the NTRK1/NGF Receptor. Cancer. Lett. 2006, 232, 90–98. - PubMed
    1. Lei L.; Parada L. F. Transcriptional Regulation of TRK Family Neurotrophin Receptors. Cell. Mol. Life Sci. 2007, 64, 522–532. - PMC - PubMed
    1. Lagadec C.; Meignan S.; Adriaenssens E.; Foveau B.; Vanhecke E.; Romon R.; Toillon R. A.; Oxombre B.; Hondermarck H.; Le Bourhis X. TRKA Overexpression Enhances Growth and Metastasis of Breast Cancer Cells. Oncogene 2009, 28, 1960–1970. - PubMed
    1. Borrello M. G.; Bongarzone I.; Pierotti M. A.; Luksch R.; Gasparini M.; Collini P.; Pilotti S.; Rizzetti M. G.; Mondellini P.; De Bernardi B.; Di Martino D.; Garaventa A.; Brisigotti M.; Tonini G. P. TRK and ret Proto-Oncogene Expression in Human Neuroblastoma Specimens: High Frequency of TRK Expression in Non-Advanced Stages. Int. J. Cancer 1993, 54, 540–545. - PubMed