Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model
In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:60 |
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| Enthalten in: |
Journal of medicinal chemistry - 60(2017), 23 vom: 14. Dez., Seite 9470-9489 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Singh, Umed [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.12.2017 Date Revised 15.01.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.7b00663 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM278105491 |
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| 100 | 1 | |a Singh, Umed |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model |
| 264 | 1 | |c 2017 | |
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| 500 | |a Date Completed 29.12.2017 | ||
| 500 | |a Date Revised 15.01.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a 4-azaindole |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Indoles |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a CDK2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.22 |2 NLM | |
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| 650 | 7 | |a Cyclin-Dependent Kinase 2 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.22 |2 NLM | |
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| 700 | 1 | |a Chashoo, Gousia |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Sameer U |e verfasserin |4 aut | |
| 700 | 1 | |a Mahajan, Priya |e verfasserin |4 aut | |
| 700 | 1 | |a Nargotra, Amit |e verfasserin |4 aut | |
| 700 | 1 | |a Mahajan, Girish |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Amarinder |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Anjna |e verfasserin |4 aut | |
| 700 | 1 | |a Mintoo, Mubashir J |e verfasserin |4 aut | |
| 700 | 1 | |a Guru, Santosh Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Aruri, Hariprasad |e verfasserin |4 aut | |
| 700 | 1 | |a Thatikonda, Thanusha |e verfasserin |4 aut | |
| 700 | 1 | |a Sahu, Promod |e verfasserin |4 aut | |
| 700 | 1 | |a Chibber, Pankaj |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Vikas |e verfasserin |4 aut | |
| 700 | 1 | |a Mir, Sameer A |e verfasserin |4 aut | |
| 700 | 1 | |a Bharate, Sonali S |e verfasserin |4 aut | |
| 700 | 1 | |a Madishetti, Sreedhar |e verfasserin |4 aut | |
| 700 | 1 | |a Nandi, Utpal |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Gurdarshan |e verfasserin |4 aut | |
| 700 | 1 | |a Mondhe, Dilip Manikrao |e verfasserin |4 aut | |
| 700 | 1 | |a Bhushan, Shashi |e verfasserin |4 aut | |
| 700 | 1 | |a Malik, Fayaz |e verfasserin |4 aut | |
| 700 | 1 | |a Mignani, Serge |e verfasserin |4 aut | |
| 700 | 1 | |a Vishwakarma, Ram A |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Parvinder Pal |e verfasserin |4 aut | |
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