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Targeting the Pim kinases in multiple myeloma.

Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M - Blood Cancer J (2015)

Bottom Line: A number of Pim inhibitors are now under development with lead compounds entering the clinic.The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM.It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

View Article: PubMed Central - PubMed

Affiliation: Apoptosis Research Centre, National University of Ireland Galway and Department of Haematology, Galway University Hospital, Galway, Ireland.

ABSTRACT
Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

No MeSH data available.


Related in: MedlinePlus

Genetic structure of the Pims. The Pim kinases share significant homology (>60%).18 Each Pim gene contains 6 exons (depicted in darker blue). Pim mRNA contains a 5' untranslated region (UTR) which is comprised of a 7 methyl-guanine cap and GC-rich region which renders the Pims ‘weak transcripts' requiring cap-dependent translation.26 The 3' UTR contains destabilizing AUUUA motifs which result in a short Pim mRNA half life.25 Pim AUG start codons are located at nucleotides 431–433 and result in translation of one and two longer isoforms of Pim-1 and Pim-2, respectively.19 The longer 44kDa isoform of Pim-1 is derived from use of an upstream CUG start codon at nucleotides 158–160 and localizes to the plasma membrane, with a role in chemotherapeutic resistance.19 Pim proteins are autophosphorylated at an upstream serine 8 residue. A threonine residue and two downstream serine residues are also present. There is no regulatory domain and the overlapping catalytic and ATP-binding domains constitute the majority of the Pim proteins.
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fig1: Genetic structure of the Pims. The Pim kinases share significant homology (>60%).18 Each Pim gene contains 6 exons (depicted in darker blue). Pim mRNA contains a 5' untranslated region (UTR) which is comprised of a 7 methyl-guanine cap and GC-rich region which renders the Pims ‘weak transcripts' requiring cap-dependent translation.26 The 3' UTR contains destabilizing AUUUA motifs which result in a short Pim mRNA half life.25 Pim AUG start codons are located at nucleotides 431–433 and result in translation of one and two longer isoforms of Pim-1 and Pim-2, respectively.19 The longer 44kDa isoform of Pim-1 is derived from use of an upstream CUG start codon at nucleotides 158–160 and localizes to the plasma membrane, with a role in chemotherapeutic resistance.19 Pim proteins are autophosphorylated at an upstream serine 8 residue. A threonine residue and two downstream serine residues are also present. There is no regulatory domain and the overlapping catalytic and ATP-binding domains constitute the majority of the Pim proteins.

Mentions: The Pim family is highly conserved with greater than 60% homology between each member12 and the genetic structure is outlined in Figure 1. Pims lack a regulatory domain and thus are constitutively active.13, 14 Pims have a unique structure divergent from that of other kinases with two proline residues located in the hinge region.13 Only one hydrogen bond is formed with ATP, with implications for drug development as the majority of ATP-competitive inhibitors form two. The Km (concentration of substrate that leads to half maximal velocity) of Pim-2 for ATP is up to 100-fold lower than that of Pim-1 and Pim-315 making a pan-inhibitor more challenging to develop than specific inhibitors.15, 16


Targeting the Pim kinases in multiple myeloma.

Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M - Blood Cancer J (2015)

Genetic structure of the Pims. The Pim kinases share significant homology (>60%).18 Each Pim gene contains 6 exons (depicted in darker blue). Pim mRNA contains a 5' untranslated region (UTR) which is comprised of a 7 methyl-guanine cap and GC-rich region which renders the Pims ‘weak transcripts' requiring cap-dependent translation.26 The 3' UTR contains destabilizing AUUUA motifs which result in a short Pim mRNA half life.25 Pim AUG start codons are located at nucleotides 431–433 and result in translation of one and two longer isoforms of Pim-1 and Pim-2, respectively.19 The longer 44kDa isoform of Pim-1 is derived from use of an upstream CUG start codon at nucleotides 158–160 and localizes to the plasma membrane, with a role in chemotherapeutic resistance.19 Pim proteins are autophosphorylated at an upstream serine 8 residue. A threonine residue and two downstream serine residues are also present. There is no regulatory domain and the overlapping catalytic and ATP-binding domains constitute the majority of the Pim proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526774&req=5

fig1: Genetic structure of the Pims. The Pim kinases share significant homology (>60%).18 Each Pim gene contains 6 exons (depicted in darker blue). Pim mRNA contains a 5' untranslated region (UTR) which is comprised of a 7 methyl-guanine cap and GC-rich region which renders the Pims ‘weak transcripts' requiring cap-dependent translation.26 The 3' UTR contains destabilizing AUUUA motifs which result in a short Pim mRNA half life.25 Pim AUG start codons are located at nucleotides 431–433 and result in translation of one and two longer isoforms of Pim-1 and Pim-2, respectively.19 The longer 44kDa isoform of Pim-1 is derived from use of an upstream CUG start codon at nucleotides 158–160 and localizes to the plasma membrane, with a role in chemotherapeutic resistance.19 Pim proteins are autophosphorylated at an upstream serine 8 residue. A threonine residue and two downstream serine residues are also present. There is no regulatory domain and the overlapping catalytic and ATP-binding domains constitute the majority of the Pim proteins.
Mentions: The Pim family is highly conserved with greater than 60% homology between each member12 and the genetic structure is outlined in Figure 1. Pims lack a regulatory domain and thus are constitutively active.13, 14 Pims have a unique structure divergent from that of other kinases with two proline residues located in the hinge region.13 Only one hydrogen bond is formed with ATP, with implications for drug development as the majority of ATP-competitive inhibitors form two. The Km (concentration of substrate that leads to half maximal velocity) of Pim-2 for ATP is up to 100-fold lower than that of Pim-1 and Pim-315 making a pan-inhibitor more challenging to develop than specific inhibitors.15, 16

Bottom Line: A number of Pim inhibitors are now under development with lead compounds entering the clinic.The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM.It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

View Article: PubMed Central - PubMed

Affiliation: Apoptosis Research Centre, National University of Ireland Galway and Department of Haematology, Galway University Hospital, Galway, Ireland.

ABSTRACT
Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

No MeSH data available.


Related in: MedlinePlus