Structural Optimization and Structure–Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants

Pan, Shulei; Zhang, Liting; Luo, Xiaoman; Nan, Jinshan; Bin, Huachao; Yang, Li; Huang, Qiao; Wang, Tianqi; Pan, Zhiling; Mu, Bo; Wang, Falu; Tian, Chuanshan; Liu, Yang; Li, Linli; Yang, Shengyong

doi:10.1021/acs.jmedchem.1c01597

Cited by 20 publications

(16 citation statements)

References 78 publications

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“…Interestingly, it was noted that TRK total protein decreased at high concentration JND4135 treatment in some BaF3-TRKs cells, especially the TRKC fusion proteins ( Figure 2 and Figure S2 ), which were consistent with reported data of TRK inhibitors by some other groups [ 17 , 25 , 26 , 27 ].…”

Section: Resultssupporting

confidence: 90%

JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo

et al. 2022

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The tropomyosin receptor kinases (TRKs) have been validated as effective targets in anticancer drug discovery. Two first-generation TRK inhibitors have been approved into market and displayed an encouraging therapeutic response in cancer patients harboring TRK fusion proteins. However, acquired resistance mediated by secondary TRK mutations especially in the xDFG motif remains an unsolved challenge in the clinic. Herein, we report the preclinical pharmacological results of JND4135, a new type II pan-TRK inhibitor, in overcoming TRK mutant resistance, including the xDFG mutations in vitro and in vivo. At a low nanomolar level, JND4135 displays a strong activity against wild-type TRKA/B/C and secondary mutations involving xDFG motif substitutions in kinase assays and cellular models; occupies the TRK proteins for an extended time; and has a slower dissociation rate than other TRK inhibitors. Moreover, by intraperitoneal injection, JND4135 exhibits tumor growth inhibition (TGI) of 81.0% at a dose of 40 mg/kg in BaF3-CD74-TRKA-G667C mice xenograft model. Therefore, JND4135 can be considered as a lead compound for drug discovery overcoming the resistance of TRK inhibitor drugs mediated by xDFG mutations.

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Section: Resultssupporting

confidence: 90%

JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo

et al. 2022

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“… 50 However, repotrectinib can overcome gatekeeper and solvent-front mutations, it remains insensitive to NTRK1 G667C and NTRK3 G696C in DGF motifs. 82 …”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

“…50 However, repotrectinib can overcome gatekeeper and solvent-front mutations, it remains insensitive to NTRK1 G667C and NTRK3 G696C in DGF motifs. 82 In general, resistance mutations may overlap and vary between TKIs, which may be related to the types of the kinase. Therefore, if a resistance mutation occurs during TKI therapy, changing the TKI may be helpful.…”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Yang

Wang

et al. 2022

Sig Transduct Target Ther

110

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Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.

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“…108 The docking results illustrate that the “linker” moiety of pyrazolo[1,5- a ]pyrimidine is anchored to the hinge region through a key H-bond with the NH of Met592 while forming a CH−π interaction with Val524. 109…”

Section: Pyrazole-containing Drugs Targeting Central Nervous System D...mentioning

confidence: 99%

Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies

Yao

et al. 2022

RSC Med. Chem.

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Structural Optimization and Structure–Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants

Cited by 20 publications

References 78 publications

JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo

JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies

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