Masitinib le nouveau paradigme du 13/09/2019

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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.

[Eur J Med Chem. 2019]

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