Discovery of 4-anilino α-carbolines as novel Brk inhibitors

Mahmoud, Kazem; Krug, Martin; Wersig, Tom; Slynko, Inna; Schächtele, Christoph; Totzke, Frank; Sippl, Wolfgang; Hilgeroth, Andreas

doi:10.1016/j.bmcl.2014.03.002

Cited by 22 publications

(18 citation statements)

References 19 publications

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“…Kinase selectivity of an inhibitor was related to the number of hinge hydrogen bonds between the kinase and the kinase inhibitor and the space usage in the ATP-binding pocket (50). Several developed BRK inhibitors showed three hydrogen bonds with the hinge region of BRK in the predicted binding mode (17,18). On the basis of molecular docking studies, XMU-MP-2 is predicted to form five hydrogen bonds with the BRK kinase.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, several small-molecule inhibitors of BRK were reported with biochemical activities and limited cellular results (17)(18)(19). However, these compounds have not been used to investigate the impact of BRK inhibition on cancer cell signaling, nor in vivo potential therapeutic efficacy on BRK-positive cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Compound 4f ( Supplementary Fig. S1), a derivative of 4anilino-pyrido [2,3-b]indoles, was used as the control, which was reported with the IC 50 of 3.2 nmol/L of inhibiting BRK in a biochemical assay (18). In BRK-transformed Ba/F3 cells, XMU-MP-2 inhibited the autophosphorylation of BRK at the site of Y342 in a dose-dependent manner and the maximum inhibition was observed starting at the concentration of 500 nmol/L ( Fig.…”

Section: Xmu-mp-2 Identification and Optimizationmentioning

confidence: 99%

“…Directly targeting kinase activity by using small molecules or knockdown the expression of BRK were reported by several groups (2,(17)(18)(19)(20)(21); however, the question whether the small-molecule BRK inhibitor can be effectively used in breast cancer with elevated BRK expression has not been thoroughly addressed both in cell and in animal models. In addition, BRK expression is independent of ER/PR/HER2 expression, which may suggest a potential therapeutic opportunity whether the inhibition of BRK combining with relevant target therapeutics could address the challenge of the treatment for aggressive ER/PR/HER2 negative breast cancers or overcome the drug resistance against ER/PR/ HER2-targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

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Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors

Jiang

Gui

et al. 2017

Cancer Research

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Approximately 80% of breast cancers overexpress the kinase breast tumor kinase (BRK)/protein tyrosine kinase 6, which has various oncogenic roles in breast cancer cell proliferation, survival, and migration. However, BRK inhibitors have yet to be explored as possible therapeutic tools. In this study, we used a parallel compound-centric approach to discover a new class of pharmaceutical agents, exemplified by XMU-MP-2, as potent and selective BRK inhibitors. XMU-MP-2 exhibited target-specific inhibition of BRK kinase activity and disrupted signaling pathways mediated by this activity, thereby reducing proliferation in BRK-positive breast cancer cells. In mouse xenograft models, XMU-MP-2 repressed the growth of tumors driven by oncogenic BRK, including BRK-transformed Ba/F3 cells and BRK-positive breast cancer cells. Notably, XMU-MP-2 cooperated strongly with HER2 inhibitor or ER blockade to block breast cancer cell proliferation in vitro and in vivo Overall, our findings offer a preclinical proof of concept for therapeutic targeting of the BRK kinase in breast cancer. Cancer Res; 77(1); 175-86. ©2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Xmu-mp-2 Identification and Optimizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors

Jiang

Gui

et al. 2017

Cancer Research

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“…Imidazo[1,2-a]pyrazin-8-amines and 4-anilino α-carbolines were also identified as PTK6-selective inhibitors that block its catalytic activity (16,17). In the present study, pyrazolopyrimidine (PP)1 [4-amino-5-(4-methylphenyl)-7-(t-butyl) pyrazolo [3,4- The associated pyrazolopyrimidines PP1 and PP2 inhibit protein tyrosine kinase 6 activity and suppress breast cancer cell proliferation it was then examined whether these compounds inhibited PTK6-dependent signaling processes and the proliferation of breast carcinoma T-47D cells.…”

Section: Introductionmentioning

confidence: 99%

The associated pyrazolopyrimidines PP1 and PP2 inhibit protein tyrosine kinase 6 activity and suppress breast cancer cell proliferation

2017

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Abstract. Protein tyrosine kinase (PTK)6, also known as breast tumor kinase, is a non-receptor tyrosine kinase. It is closely associated with, but evolutionarily distinct from, the Src family members. PTK6 has a role in proliferation, migration and invasion in various cancers, and therefore has been suggested as a potentially valuable therapeutic target. In an attempt to develop PTK6 inhibitors, chemicals known to inhibit various kinases were screened for their ability to inhibit PTK6. Pyrazolopyrimidine (PP)1, PP2 and a lymphocyte-specific protein tyrosine kinase inhibitor strongly inhibited the catalytic activity of PTK6 in vitro. These chemicals suppressed the phosphorylation of PTK6 substrate proteins, including signal transducer and activator of transcription 3, in human embryonic kidney (HEK) 293 cells expressing hyperactive PTK6. They also expressed selectivity towards PTK6 over other PTK members in HEK 293 cells. PP1 and PP2 specifically inhibited the PTK6-dependent proliferation of human breast carcinoma T-47D cells. PP1 and PP2 were more selective for PTK6 than for Src family kinases, and may be useful for the treatment of PTK6-positive malignant diseases such as breast cancer.

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Nucleophilic Halogenation of HeterocyclicN‐Oxides: Recent Progress and a Practical Guide

Malykhin

Sukhorukov

2021

Adv Synth Catal

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The review summarizes recent advances in the synthesis of C2‐halogenated nitrogen heterocycles via nucleophilic halogenation of corresponding N‐oxides as well as application of this methodology in the synthesis of pharmaceuticals. Both scientific and patent literature is reviewed mostly over the period of the last ten years. The review contains a practical guide (typical procedures and infographic based on extensive literature analysis), which can help practitioners in choosing optimal reagents/conditions for nucleophilic halogenation of N‐heterocycles of different types. The bibliography contains 199 references.

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Discovery of 4-anilino α-carbolines as novel Brk inhibitors

Cited by 22 publications

References 19 publications

Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors

Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors

The associated pyrazolopyrimidines PP1 and PP2 inhibit protein tyrosine kinase 6 activity and suppress breast cancer cell proliferation

Nucleophilic Halogenation of HeterocyclicN‐Oxides: Recent Progress and a Practical Guide

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