Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers.
OBJECTIVE
PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematologic malignancies.


METHODS
Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low Km for ATP and, thus, requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context.


RESULTS
LGB321 is active on PIM2-dependent multiple myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non-Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with cytarabine in this model.


CONCLUSIONS
We have developed a potent and selective pan-PIM inhibitor with single-agent antiproliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematologic malignancies.
Authors' Affiliations: Oncology Disease Area Research; Global Discovery Chemistry/Oncology and Exploratory Chemistry; MAP Group; Chemical and Pharmaceutical Profiling Group, Novartis Institutes for Biomedical Research, Emeryville, California; Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts; Oncology Disease Area Research; and Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Pablo D
PD
Garcia
John L
JL
Langowski
Yingyun
Y
Wang
Min
M
Chen
Joseph
J
Castillo
Christie
C
Fanton
Marjorie
M
Ison
Tatiana
T
Zavorotinskaya
Yumin
Y
Dai
Jing
J
Lu
Xiao-Hong
XH
Niu
Stephen
S
Basham
Julie
J
Chan
Jianjun
J
Yu
Michael
M
Doyle
Paul
P
Feucht
Robert
R
Warne
Jamie
J
Narberes
Tiffany
T
Tsang
Christine
C
Fritsch
Audrey
A
Kauffmann
Estelle
E
Pfister
Peter
P
Drueckes
Joerg
J
Trappe
Christopher
C
Wilson
Wooseok
W
Han
Jiong
J
Lan
Gisele
G
Nishiguchi
Mika
M
Lindvall
Cornelia
C
Bellamacina
J Alex
JA
Aycinena
Richard
R
Zang
Jocelyn
J
Holash
Matthew T
MT
Burger
D000818:Animals; D045744:Cell Line, Tumor; D019337:Hematologic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C490587:PIM2 protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C546842:MTOR protein, human; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D058570:TOR Serine-Threonine Kinases