Mechanistic Investigation of Thiazole-Based Pyruvate Kinase M2 Inhibitor Causing Tumor Regression in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is a deadly breast cancer with a poor prognosis. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, is abnormally highly expressed in TNBC. Overexpressed PKM2 amplifies glucose uptake, enhances lactate production, and suppresses autophagy, thereby expediting the progression of oncogenic processes. A high mortality rate demands novel chemotherapeutic regimens at once. Herein, we report the rational development of an imidazopyridine-based thiazole derivative 7d as an anticancer agent inhibiting PKM2. Nanomolar range PKM2 inhibitors with favorable drug-like properties emerged through enzyme assays. Experiments on two-dimensional (2D)/three-dimensional (3D) cell cultures, lactate release assay, surface plasmon resonance (SPR), and quantitative real-time polymerase chain reaction (qRT-PCR) validated 7d preclinically. In vivo, 7d outperformed lapatinib in tumor regression. This investigation introduces a lead-based approach characterized by its clear-cut chemistry and robust efficacy in designing an exceptionally potent inhibitor targeting PKM2, with a focus on combating TNBC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
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| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 5 vom: 14. März, Seite 3339-3357 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Das, Rudradip [VerfasserIn] |
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| Links: |
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| Themen: |
0VUA21238F |
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| Anmerkungen: |
Date Completed 15.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c01512 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368979938 |
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| 520 | |a Triple-negative breast cancer (TNBC) is a deadly breast cancer with a poor prognosis. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, is abnormally highly expressed in TNBC. Overexpressed PKM2 amplifies glucose uptake, enhances lactate production, and suppresses autophagy, thereby expediting the progression of oncogenic processes. A high mortality rate demands novel chemotherapeutic regimens at once. Herein, we report the rational development of an imidazopyridine-based thiazole derivative 7d as an anticancer agent inhibiting PKM2. Nanomolar range PKM2 inhibitors with favorable drug-like properties emerged through enzyme assays. Experiments on two-dimensional (2D)/three-dimensional (3D) cell cultures, lactate release assay, surface plasmon resonance (SPR), and quantitative real-time polymerase chain reaction (qRT-PCR) validated 7d preclinically. In vivo, 7d outperformed lapatinib in tumor regression. This investigation introduces a lead-based approach characterized by its clear-cut chemistry and robust efficacy in designing an exceptionally potent inhibitor targeting PKM2, with a focus on combating TNBC | ||
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| 650 | 7 | |a Lactates |2 NLM | |
| 700 | 1 | |a Pulugu, Priyanka |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Aditya A |e verfasserin |4 aut | |
| 700 | 1 | |a Chatterjee, Deep Rohan |e verfasserin |4 aut | |
| 700 | 1 | |a Baviskar, Shraddha |e verfasserin |4 aut | |
| 700 | 1 | |a Vyas, Het |e verfasserin |4 aut | |
| 700 | 1 | |a Behera, Santosh Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Srivastava, Akshay |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Hemant |e verfasserin |4 aut | |
| 700 | 1 | |a Shard, Amit |e verfasserin |4 aut | |
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