The HCK/BTK inhibitor KIN-8194 is active in MYD88-driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance.
Adenine
/ analogs & derivatives
Agammaglobulinaemia Tyrosine Kinase
/ antagonists & inhibitors
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Female
Humans
Lymphoma
/ drug therapy
Mice, Inbred NOD
Mice, SCID
Mutation
/ drug effects
Myeloid Differentiation Factor 88
/ genetics
Piperidines
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-hck
/ antagonists & inhibitors
Tumor Cells, Cultured
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
18 11 2021
18 11 2021
Historique:
received:
26
02
2021
accepted:
27
05
2021
pubmed:
17
6
2021
medline:
25
12
2021
entrez:
16
6
2021
Statut:
ppublish
Résumé
Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)-mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481, particularly BTKCys481Ser, are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88-mutated lymphoma cells, including ibrutinib-resistant BTKCys481Ser-expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained inhibition of HCK and BTK for 24 hours after single oral administration of KIN-8194 in an MYD88-mutated TMD-8 activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) and BCWM.1 Waldenström macroglobulinemia (WM) xenografted mice with wild-type BTK (BTKWT)- or BTKCys481Ser-expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT- and BTKCys481Ser-expressing TMD-8 DLBCL xenografted mice, including sustained complete responses of >12 weeks off treatment in mice with BTKWT-expressing TMD-8 tumors. The BCL_2 inhibitor venetoclax enhanced the antitumor activity of KIN-8194 in BTKWT- and BTKCys481Ser-expressing MYD88-mutated lymphoma cells and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser-expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK.
Identifiants
pubmed: 34132782
pii: S0006-4971(21)01236-2
doi: 10.1182/blood.2021011405
pmc: PMC8602936
doi:
Substances chimiques
Antineoplastic Agents
0
Myeloid Differentiation Factor 88
0
Piperidines
0
Protein Kinase Inhibitors
0
ibrutinib
1X70OSD4VX
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
Proto-Oncogene Proteins c-hck
EC 2.7.10.2
Adenine
JAC85A2161
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1966-1979Subventions
Organisme : NCI NIH HHS
ID : P50 CA100707
Pays : United States
Informations de copyright
© 2021 by The American Society of Hematology.
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