i.e., c-KIT (Kd ¼ 78 nM) and CFS-1R (Kd ¼ 30 nM) [11, 158]. On the other hand,
crenolanib (63) does not inhibit any other known tyrosine or serine/threonine kinase
at clinically achievable concentrations [134, 158].
This class of benzimidazole TKIs (Fig. 20) was first described by Pfizer in 2001
(WO0140217A1) as antiproliferative and antiangiogenic agents, showing IC 50
values in the nanomolar range for PDGFR-β inhibition. Although no structureactivity relationship is described for this series, the most promising derivatives
from this research effort, i.e., crenolanib (63, CP-868,596) [134] and CP-673,451
(64) [160], clearly share common structural features and similar inhibitory potencies
against PDGFRs, differing exclusively in the ether side chain (Fig. 20).
The promising antiangiogenic properties and adequate safety and pharmacokinetic profiles described for crenolanib (63) during preclinical studies encouraged
further clinical trials. Phase I clinical evaluation of crenolanib (63) in humans
indicates an optimal and well-tolerated dose regimen of 100 mg twice daily, with
nausea and vomiting as the most frequent adverse effects, which are, however,
mitigated by concomitant food ingestion [134]. AROG Pharmaceuticals licensed
this drug candidate from Pfizer in April 2010.
Crenolanib (63) is currently undergoing multiple phase II and III clinical trials, as
a single agent or in combination with known antitumor drugs, for acute myeloid
leukemia (AML, NCT01522469, NCT01657682, NCT02400281), gastrointestinal
stromal tumor (GIST; NCT01243346, NCT02847429), and glioma treatments
(NCT01229644, NCT01393912) [11, 136, 158].
Biochemical studies clearly demonstrated that this prototype acts as a type I TKI,
presenting greater affinity to the target kinases’ active states. For instance, crenolanib
(63) showed tenfold higher affinity to active FLT3 (Kd ¼ 0.7 nM) versus autoinhibited FLT3 (Kd ¼ 6.7 nM) [11].
Considering that active states are often derived from the gain-of-function mutations of PDGFR-encoding genes, crenolanib (63) represents a promising alternative
for patients with PDGFR mutations, especially those that render the kinase domain
constitutively phosphorylated, causing acquired resistance to imatinib (60) and other
type II TKIs, such as sorafenib (42) and nilotinib (61) [11, 152].
In this context, crenolanib (63) was described by Heinrich and colleagues as the
most potent PDGFR-α D842V kinase inhibitor identified so far, with an IC 50 in a
range of 10 nM, being at least 100-fold more potent than imatinib (60). Moreover,
the prototype retained its inhibitory activity when the gatekeeper T674I mutation
was added to the D842V mutated protein. Similar to the biochemical assay results,
compound 63 was significantly more potent (IC 50 ¼ 22 nM) than imatinib (60;
IC 50 ¼ 1,510 nM) against BaF3 D842V cell line proliferation [158].
Moreover, this highly selective inhibitor of class III RTKs is expected to show
reduced toxicity in comparison with other nonselective multi-kinase inhibitors,
demonstrating that type I inhibitors are not necessarily associated with lack of
selectivity [152]. However, the exact molecular reasons for this impressive selectivity profile remain yet to be elucidated. Representing the first example of a potent and
highly selective type I TKI, crenolanib (63) may characterize a novel breakthrough
in target therapy in cancer [159].
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
189
crenolanib (63) does not inhibit any other known tyrosine or serine/threonine kinase
at clinically achievable concentrations [134, 158].
This class of benzimidazole TKIs (Fig. 20) was first described by Pfizer in 2001
(WO0140217A1) as antiproliferative and antiangiogenic agents, showing IC 50
values in the nanomolar range for PDGFR-β inhibition. Although no structureactivity relationship is described for this series, the most promising derivatives
from this research effort, i.e., crenolanib (63, CP-868,596) [134] and CP-673,451
(64) [160], clearly share common structural features and similar inhibitory potencies
against PDGFRs, differing exclusively in the ether side chain (Fig. 20).
The promising antiangiogenic properties and adequate safety and pharmacokinetic profiles described for crenolanib (63) during preclinical studies encouraged
further clinical trials. Phase I clinical evaluation of crenolanib (63) in humans
indicates an optimal and well-tolerated dose regimen of 100 mg twice daily, with
nausea and vomiting as the most frequent adverse effects, which are, however,
mitigated by concomitant food ingestion [134]. AROG Pharmaceuticals licensed
this drug candidate from Pfizer in April 2010.
Crenolanib (63) is currently undergoing multiple phase II and III clinical trials, as
a single agent or in combination with known antitumor drugs, for acute myeloid
leukemia (AML, NCT01522469, NCT01657682, NCT02400281), gastrointestinal
stromal tumor (GIST; NCT01243346, NCT02847429), and glioma treatments
(NCT01229644, NCT01393912) [11, 136, 158].
Biochemical studies clearly demonstrated that this prototype acts as a type I TKI,
presenting greater affinity to the target kinases’ active states. For instance, crenolanib
(63) showed tenfold higher affinity to active FLT3 (Kd ¼ 0.7 nM) versus autoinhibited FLT3 (Kd ¼ 6.7 nM) [11].
Considering that active states are often derived from the gain-of-function mutations of PDGFR-encoding genes, crenolanib (63) represents a promising alternative
for patients with PDGFR mutations, especially those that render the kinase domain
constitutively phosphorylated, causing acquired resistance to imatinib (60) and other
type II TKIs, such as sorafenib (42) and nilotinib (61) [11, 152].
In this context, crenolanib (63) was described by Heinrich and colleagues as the
most potent PDGFR-α D842V kinase inhibitor identified so far, with an IC 50 in a
range of 10 nM, being at least 100-fold more potent than imatinib (60). Moreover,
the prototype retained its inhibitory activity when the gatekeeper T674I mutation
was added to the D842V mutated protein. Similar to the biochemical assay results,
compound 63 was significantly more potent (IC 50 ¼ 22 nM) than imatinib (60;
IC 50 ¼ 1,510 nM) against BaF3 D842V cell line proliferation [158].
Moreover, this highly selective inhibitor of class III RTKs is expected to show
reduced toxicity in comparison with other nonselective multi-kinase inhibitors,
demonstrating that type I inhibitors are not necessarily associated with lack of
selectivity [152]. However, the exact molecular reasons for this impressive selectivity profile remain yet to be elucidated. Representing the first example of a potent and
highly selective type I TKI, crenolanib (63) may characterize a novel breakthrough
in target therapy in cancer [159].
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
189