4.3 PDGFR Inhibitors
Considering the relevance of the PDGFR pathway for tumor establishment, growth,
and aggressiveness, the development of PDGFR inhibitors has become a promising
therapeutic approach in cancer treatment. This inhibition is achieved by three main
strategies, i.e., antagonism with specific antibodies directed to the protein extracellular (EC) domain; sequestration of PDGF isoforms by soluble extracellular parts of
the receptors, preventing their binding to cellular PDGFRs; and direct inhibition of
the enzymatic activity by the well-known TKIs [133].
Several potent inhibitors of PDGFR kinase activity are available for therapeutic
use (Fig. 18) or under preclinical and clinical evaluation [7, 10]. Up to now, none of
the approved inhibitors are highly selective for this target, but, in turn, they inhibit
several structurally related tyrosine kinases, showing particular selectivity profiles
depending on their binding modes to the TK domain [3, 133].
The first PDGFR inhibitor approved for clinical use was imatinib (60), which also
inhibits the stem cell receptor c-KIT and Abl kinases. However, imatinib (60)
treatment in PDGFR-dependent tumors has recurrently been associated with primary
and secondary resistance and disease progression. Second-line drugs include
approved multi-kinase inhibitors, such as sorafenib (42) and sunitinib (43)
(Fig. 18). For instance, sunitinib (43, SU11248; Sutent™; Pfizer) was approved by
FDA in 2006 for imatinib-refractory GIST patients, although not all imatinibresistant patients benefit from this drug [3, 148, 151].
Moreover, considering the relevance of PDGFRs as therapeutic targets for cancer
treatment, selective drug candidates rationally designed to act as PDGFR inhibitors
are under development in ongoing clinical trials. The most advanced prototype is
crenolanib (63; Fig. 20), a TKI designed to target PDGFRα/β [152] which is
currently in clinical development for acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma treatments [11].
4.3.1 Imatinib: The First PDGFR TKI
Imatinib (60, STI571; Glivec™ or Gleevec™; Novartis) is a small-molecule tyrosine
kinase inhibitor (TKI) belonging to the 2-phenylaminopyrimidine chemical class
[3, 153]. It was originally described by Druker and colleagues in 1996 as a potent
inhibitor of the fusion BCR-ABL oncoprotein, which is associated with chronic
myeloid leukemia (CML) and other types of Philadelphia chromosome-positive
leukemias [4, 153, 154]. Therefore, this drug received its first approval by FDA in
2001 for treatment of CML [3, 155]. Later, the receptor tyrosine kinases (RTKs)
PDGFR-α, PDGFR-β, and KIT were also found to be potently inhibited by 60,
resulting in an additional approval of this drug in 2002 for advanced GISTs, taking
into account the important role of KIT and PDGFR in the pathogenesis of this type of
cancer [3, 4, 155]. Several other therapeutic uses were further established for
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
185
Considering the relevance of the PDGFR pathway for tumor establishment, growth,
and aggressiveness, the development of PDGFR inhibitors has become a promising
therapeutic approach in cancer treatment. This inhibition is achieved by three main
strategies, i.e., antagonism with specific antibodies directed to the protein extracellular (EC) domain; sequestration of PDGF isoforms by soluble extracellular parts of
the receptors, preventing their binding to cellular PDGFRs; and direct inhibition of
the enzymatic activity by the well-known TKIs [133].
Several potent inhibitors of PDGFR kinase activity are available for therapeutic
use (Fig. 18) or under preclinical and clinical evaluation [7, 10]. Up to now, none of
the approved inhibitors are highly selective for this target, but, in turn, they inhibit
several structurally related tyrosine kinases, showing particular selectivity profiles
depending on their binding modes to the TK domain [3, 133].
The first PDGFR inhibitor approved for clinical use was imatinib (60), which also
inhibits the stem cell receptor c-KIT and Abl kinases. However, imatinib (60)
treatment in PDGFR-dependent tumors has recurrently been associated with primary
and secondary resistance and disease progression. Second-line drugs include
approved multi-kinase inhibitors, such as sorafenib (42) and sunitinib (43)
(Fig. 18). For instance, sunitinib (43, SU11248; Sutent™; Pfizer) was approved by
FDA in 2006 for imatinib-refractory GIST patients, although not all imatinibresistant patients benefit from this drug [3, 148, 151].
Moreover, considering the relevance of PDGFRs as therapeutic targets for cancer
treatment, selective drug candidates rationally designed to act as PDGFR inhibitors
are under development in ongoing clinical trials. The most advanced prototype is
crenolanib (63; Fig. 20), a TKI designed to target PDGFRα/β [152] which is
currently in clinical development for acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma treatments [11].
4.3.1 Imatinib: The First PDGFR TKI
Imatinib (60, STI571; Glivec™ or Gleevec™; Novartis) is a small-molecule tyrosine
kinase inhibitor (TKI) belonging to the 2-phenylaminopyrimidine chemical class
[3, 153]. It was originally described by Druker and colleagues in 1996 as a potent
inhibitor of the fusion BCR-ABL oncoprotein, which is associated with chronic
myeloid leukemia (CML) and other types of Philadelphia chromosome-positive
leukemias [4, 153, 154]. Therefore, this drug received its first approval by FDA in
2001 for treatment of CML [3, 155]. Later, the receptor tyrosine kinases (RTKs)
PDGFR-α, PDGFR-β, and KIT were also found to be potently inhibited by 60,
resulting in an additional approval of this drug in 2002 for advanced GISTs, taking
into account the important role of KIT and PDGFR in the pathogenesis of this type of
cancer [3, 4, 155]. Several other therapeutic uses were further established for
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
185