ZYBT1, a potent, irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer
Abstract Bruton's tyrosine kinase (BTK) plays a central and pivotal role in controlling the pathways involved in the pathobiology of cancer, rheumatoid arthritis (RA), and other autoimmune disorders. ZYBT1 is a potent, irreversible, specific BTK inhibitor that inhibits the ibrutinib‐resistant C...
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.565 |
| _version_ | 1818848742909935616 |
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| author | Krishnarup Ghoshdastidar Hoshang Patel Hitesh Bhayani Ankit Patel Kinjal Thakkar Dinesh Patel Manoranjan Sharma Jaideep Singh Jogeswar Mohapatra Abhijit Chatterjee Dipam Patel Rajesh Bahekar Rajiv Sharma Lakshmikant Gupta Nirmal Patel Poonam Giri Nuggehally R. Srinivas Mukul Jain Debdutta Bandyopadhyay Pankaj R. Patel Ranjit C. Desai |
| author_facet | Krishnarup Ghoshdastidar Hoshang Patel Hitesh Bhayani Ankit Patel Kinjal Thakkar Dinesh Patel Manoranjan Sharma Jaideep Singh Jogeswar Mohapatra Abhijit Chatterjee Dipam Patel Rajesh Bahekar Rajiv Sharma Lakshmikant Gupta Nirmal Patel Poonam Giri Nuggehally R. Srinivas Mukul Jain Debdutta Bandyopadhyay Pankaj R. Patel Ranjit C. Desai |
| author_sort | Krishnarup Ghoshdastidar |
| collection | DOAJ |
| description | Abstract Bruton's tyrosine kinase (BTK) plays a central and pivotal role in controlling the pathways involved in the pathobiology of cancer, rheumatoid arthritis (RA), and other autoimmune disorders. ZYBT1 is a potent, irreversible, specific BTK inhibitor that inhibits the ibrutinib‐resistant C481S BTK with nanomolar potency. ZYBT1 is found to be a promising molecule to treat both cancer and RA. In the present report we profiled the molecule for in‐vitro, in‐vivo activity, and pharmacokinetic properties. ZYBT1 inhibits BTK and C481S BTK with an IC50 of 1 nmol/L and 14 nmol/L, respectively, inhibits the growth of various leukemic cell lines with IC50 of 1 nmol/L to 15 μmol/L, blocks the phosphorylation of BTK and PLCγ2, and inhibits secretion of TNF‐α, IL‐8 and IL‐6. It has favorable pharmacokinetic properties suitable for using as an oral anti‐cancer and anti‐arthritic drug. In accordance with the in‐vitro properties, it demonstrated robust efficacy in murine models of collagen‐induced arthritis (CIA) and streptococcal cell wall (SCW) induced arthritis. In both models, ZYBT1 alone could suppress the progression of the diseases. It also reduced the growth of TMD8 xenograft tumor. The results suggested that ZYBT1 has high potential for treating RA, and cancer. |
| first_indexed | 2024-12-19T06:22:11Z |
| format | Article |
| id | doaj.art-426ccabb23744fc0aceb0a7d29b505f0 |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-12-19T06:22:11Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-426ccabb23744fc0aceb0a7d29b505f02022-12-21T20:32:39ZengWileyPharmacology Research & Perspectives2052-17072020-08-0184n/an/a10.1002/prp2.565ZYBT1, a potent, irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancerKrishnarup Ghoshdastidar0Hoshang Patel1Hitesh Bhayani2Ankit Patel3Kinjal Thakkar4Dinesh Patel5Manoranjan Sharma6Jaideep Singh7Jogeswar Mohapatra8Abhijit Chatterjee9Dipam Patel10Rajesh Bahekar11Rajiv Sharma12Lakshmikant Gupta13Nirmal Patel14Poonam Giri15Nuggehally R. Srinivas16Mukul Jain17Debdutta Bandyopadhyay18Pankaj R. Patel19Ranjit C. Desai20Department of Cell Biology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Cell Biology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Cell Biology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Cell Biology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Cell Biology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Medicinal Chemistry Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Medicinal Chemistry Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Medicinal Chemistry Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacokinetics Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacokinetics Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacokinetics Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacokinetics Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Pharmacology and Toxicology Zydus Research Center Ahmedabad Gujarat IndiaDepartment of Cell Biology Zydus Research Center Ahmedabad Gujarat IndiaZydus Research Center Ahmedabad Gujarat IndiaDepartment of Medicinal Chemistry Zydus Research Center Ahmedabad Gujarat IndiaAbstract Bruton's tyrosine kinase (BTK) plays a central and pivotal role in controlling the pathways involved in the pathobiology of cancer, rheumatoid arthritis (RA), and other autoimmune disorders. ZYBT1 is a potent, irreversible, specific BTK inhibitor that inhibits the ibrutinib‐resistant C481S BTK with nanomolar potency. ZYBT1 is found to be a promising molecule to treat both cancer and RA. In the present report we profiled the molecule for in‐vitro, in‐vivo activity, and pharmacokinetic properties. ZYBT1 inhibits BTK and C481S BTK with an IC50 of 1 nmol/L and 14 nmol/L, respectively, inhibits the growth of various leukemic cell lines with IC50 of 1 nmol/L to 15 μmol/L, blocks the phosphorylation of BTK and PLCγ2, and inhibits secretion of TNF‐α, IL‐8 and IL‐6. It has favorable pharmacokinetic properties suitable for using as an oral anti‐cancer and anti‐arthritic drug. In accordance with the in‐vitro properties, it demonstrated robust efficacy in murine models of collagen‐induced arthritis (CIA) and streptococcal cell wall (SCW) induced arthritis. In both models, ZYBT1 alone could suppress the progression of the diseases. It also reduced the growth of TMD8 xenograft tumor. The results suggested that ZYBT1 has high potential for treating RA, and cancer.https://doi.org/10.1002/prp2.565Bruton's tyrosine kinasecancerirreversible inhibitorrheumatoid arthritisxenograft |
| spellingShingle | Krishnarup Ghoshdastidar Hoshang Patel Hitesh Bhayani Ankit Patel Kinjal Thakkar Dinesh Patel Manoranjan Sharma Jaideep Singh Jogeswar Mohapatra Abhijit Chatterjee Dipam Patel Rajesh Bahekar Rajiv Sharma Lakshmikant Gupta Nirmal Patel Poonam Giri Nuggehally R. Srinivas Mukul Jain Debdutta Bandyopadhyay Pankaj R. Patel Ranjit C. Desai ZYBT1, a potent, irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer Pharmacology Research & Perspectives Bruton's tyrosine kinase cancer irreversible inhibitor rheumatoid arthritis xenograft |
| title | ZYBT1, a potent, irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer |
| title_full | ZYBT1, a potent, irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer |
| title_fullStr | ZYBT1, a potent, irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer |
| title_full_unstemmed | ZYBT1, a potent, irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer |
| title_short | ZYBT1, a potent, irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer |
| title_sort | zybt1 a potent irreversible bruton s tyrosine kinase btk inhibitor that inhibits the c481s btk with profound efficacy against arthritis and cancer |
| topic | Bruton's tyrosine kinase cancer irreversible inhibitor rheumatoid arthritis xenograft |
| url | https://doi.org/10.1002/prp2.565 |
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