Crenolanib

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

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]

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.

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.

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.

PDGFRα

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

[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