INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support.
Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in tumor cells and promote tumor growth, survival, and drug resistance. INCB16562 was developed as a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. The specific cellular activity of the inhibitor was demonstrated by its potent and dose-dependent inhibition of cytokine-dependent JAK/STAT signaling and cell proliferation in the absence of effects on Bcr-Abl-expressing cells. Treatment of myeloma cells with INCB16562 potently inhibited interleukin-6 (IL-6)-induced phosphorylation of STAT3. Moreover, the proliferation and survival of myeloma cells dependent on IL-6 for growth, as well as the IL-6-induced growth of primary bone marrow-derived plasma cells from a multiple myeloma patient, were inhibited by INCB16562. Induction of caspase activation and apoptosis was observed and attributed, at least in part, to the suppression of Mcl-1 expression. Importantly, INCB16562 abrogated the protective effects of recombinant cytokines or bone marrow stromal cells and sensitized myeloma cells to cell death by exposure to dexamethasone, melphalan, or bortezomib. Oral administration of INCB16562 antagonized the growth of myeloma xenografts in mice and enhanced the antitumor activity of relevant agents in combination studies. Taken together, these data suggest that INCB16562 is a potent JAK1/2 inhibitor and that mitigation of JAK/STAT signaling by targeting JAK1 and JAK2 will be beneficial in the treatment of myeloma patients, particularly in combination with other agents.
Li
Jun
J
Discovery Biology, Incyte Corporation, Wilmington, DE 19880, USA. junli@incyte.com
Favata
Margaret
M
Kelley
Jennifer A
JA
Caulder
Eian
E
Thomas
Beth
B
Wen
Xiaoming
X
Sparks
Richard B
RB
Arvanitis
Ari
A
Rogers
James D
JD
Combs
Andrew P
AP
Vaddi
Kris
K
Solomon
Kimberly A
KA
Scherle
Peggy A
PA
Newton
Robert
R
Fridman
Jordan S
JS
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008558:Melphalan / Q000008:administration & dosage; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D001381:Azepines; D001897:Boronic Acids; C549231:INCB 16562; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D050796:STAT3 Transcription Factor; D000069286:Bortezomib; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008558:Melphalan