Crenolanib

Description

Crenolanib (670220-88-9) is a potent inhibitor of PDGFR (Kdfor α = 2.1 nM; β = 3.2 nM) and FLT3 (Kd= 0.74 nM).1Crenolanib is a type I inhibitor binding only to the active kinase conformation. It showed potent activity against imatinib-resistant PDGFRα mutations D842I, D842V, D842Y, DI842-843M, and deletion I8432as well as FLT3/ITD and FLT3/D835 mutants3. Crenolanib acted synergistically with FLT3-CAR T-cells in a FLT3-ITD+AML murine xenograft model.4

Uses

Crenolanib (CP-868569) is a highly selective and potent PDGFR-α inhibitor with IC50 of 0.9 and 1.8 nM against PDGFRα and PDGFRβ, respectively.

Uses

Crenolanib (CP-868569) is a tyrosine kinase inhibitor that acts by specifically inhibiting the receptor tyrosine kinases PDGFRα and PDGFRβ. Crenolanib (CP-868569) inhibits the activity of PDGFRα D842V kinase and prevented the phosphorylation of wild type PDGFRα. Crenolanib (CP-868569) possesses potential antineoplastic activity. Crenolanib is believed to suppress PDGFR-related signal transduction pathways leading to the inhibition of tumor angiogenesis and tumor cell proliferation.

Uses

Crenolanib is an orally bioavailable, selective inhibitor of type III tyrosine kinases with nanomolar potencies against platelet-derived growth factor receptor α (PDGFRα) and PDGFRβ and Fms-related tyrosine kinase 3 (FLT3; IC50s = 11, 3.2, and 4 nM, respectively). It also inhibits medically-relevant mutant forms of these kinases, including the D842V-containing form of PDGFR and D835Y and internal tandem duplication mutations of FLT3, at nanomolar concentrations. Crenolanib is more than 100-fold selective for these kinases over other tyrosine and serine/threonine kinases. It is effective when used in cells and in vivo.[Cayman Chemical]

Definition

ChEBI: Crenolanib is a member of the class of benzimidazoles that is 1H-benzimidazole which is substituted by a 8-(4-aminopiperidin-1-yl)quinolin-2-yl group at position 1 and by a (3-methyloxetan-3-yl)methoxy group at position 5. It is an inhibitor of type III tyrosine kinases, PDGFRalpha/beta and FLT3 (IC50 of 11, 3.2, and 4 nM). Currently under clinical development for the treatment of acute myeloid leukemia. It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, an angiogenesis inhibitor, an antineoplastic agent and an apoptosis inducer. It is a member of benzimidazoles, an aromatic ether, a member of quinolines, a member of oxetanes, an aminopiperidine and a tertiary amino compound.

in vivo

target

PDGFRα

IC 50

PDGFRα: 2.1 nM (Kd); PDGFRβ: 3.2 nM (Kd); FLT3: 0.74 nM (Kd)

References

[1] NANCY L LEWIS. Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers.[J]. Journal of Clinical Oncology, 2009, 27 31: 5262-5269. DOI:10.1200/jco.2009.21.8487
[2] CATHERINE CHOY SMITH. Crenolanib is a selective type I pan-FLT3 inhibitor.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2014: 5319-5324. DOI:10.1073/pnas.1320661111
[3] MICHAEL C HEINRICH. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors.[J]. Clinical Cancer Research, 2012, 18 16: 4375-4384. DOI:10.1158/1078-0432.ccr-12-0625
[4] HARDIKKUMAR JETANI. CAR T-cells targeting FLT3 have potent activity against FLT3−ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib[J]. Leukemia, 2018, 32 5: 1168-1179. DOI:10.1038/s41375-018-0009-0