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Piperazining' the catalytic gatekeepers: unraveling the pan-inhibition of SRC kinases; LYN, FYN and BLK by masitinib.
Aljoundi AK, et al. Future Med Chem. 2019.
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Abstract
AIM: Blocking oncogenic signaling of B-cell receptor (BCR) has been explored as a viable strategy in the treatment of diffuse large B-cell lymphoma. Masitinib is shown to multitarget LYN, FYN and BLK kinases that propagate BCR signals to downstream effectors. However, the molecular mechanisms of its selectivity and pan-inhibition remain elusive.
MATERIALS & METHODS: This study therefore employed molecular dynamics simulations coupled with advanced post-molecular dynamics simulation techniques to unravel the structural mechanisms that inform the reported multitargeting ability of masitinib.
RESULTS: Molecular dynamics simulations revealed initial selective targeting of catalytic residues (Asp334/Glu335 - LYN, Asp130/Asp148/Glu54 - FYN, Asp89 - BLK) by masitinib, with high-affinity interactions via its piperazine ring at the entrance of the ATP-binding pockets, before systematic access into the hydrophobic deep pocket grooves.
CONCLUSION: Identification of these 'gatekeeper' residues could open up a novel paradigm of structure-based design of highly selective pan-inhibitors of BCR signaling in the treatment of diffuse large B-cell lymphoma.
PMID 31516031 [ - as supplied by publisher]
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2019 Sep 13. doi: 10.4155/fmc-2018-0354. [Epub ahead of print]
'Piperazining' the catalytic gatekeepers: unraveling the pan-inhibition of SRC kinases; LYN, FYN and BLK by masitinib.
Aljoundi AK1, Agoni C1, Olotu FA1, Soliman ME1.
Author information
1
Molecular Bio-computation & Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
Abstract
Aim: Blocking oncogenic signaling of B-cell receptor (BCR) has been explored as a viable strategy in the treatment of diffuse large B-cell lymphoma. Masitinib is shown to multitarget LYN, FYN and BLK kinases that propagate BCR signals to downstream effectors. However, the molecular mechanisms of its selectivity and pan-inhibition remain elusive. Materials & methods: This study therefore employed molecular dynamics simulations coupled with advanced post-molecular dynamics simulation techniques to unravel the structural mechanisms that inform the reported multitargeting ability of masitinib. Results: Molecular dynamics simulations revealed initial selective targeting of catalytic residues (Asp334/Glu335 - LYN, Asp130/Asp148/Glu54 - FYN, Asp89 - BLK) by masitinib, with high-affinity interactions via its piperazine ring at the entrance of the ATP-binding pockets, before systematic access into the hydrophobic deep pocket grooves. Conclusion: Identification of these 'gatekeeper' residues could open up a novel paradigm of structure-based design of highly selective pan-inhibitors of BCR signaling in the treatment of diffuse large B-cell lymphoma.
KEYWORDS:
B-cell receptor; BLK; FYN; LYN; SRC kinases; diffuse large B-cell lymphoma; molecular dynamics simulation; pan-inhibition
PMID: 31516031 DOI: 10.4155/fmc-2018-0354
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Identification of a new family of pyrazolo[3,4-d]pyrimidine derivatives as multitarget Fyn-Blk-Lyn inhibitors active on B- and T-lymphoma cell lines.
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