Crenolanib (CP-868-596)

Crenolanib is a next generation inhibitor of receptor tyrosine kinases with:

·         A unique chemo-type with a benzimidazole backbone

·         Preferential inhibition of phosphorylated receptors

·         Activity against wild-type and mutant receptors

·         Specificity for PDGFRα, PDGFRβ and FLT3

·         No activity against VEGFR or FGFR

The chemical name of crenolanib besylate is 4-piperidinamine, 1-[2-[5-[(3-Methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-, monobenzenesulfonate.

Preclinical

Crenolanib besylate is an orally bioavailable, selective small molecule inhibitor of type III tyrosine kinases with nanomolar potencies against platelet-derived growth factor receptors (PDGFR) (isoforms PDGFRα and PDGFRβ) and Fms-related tyrosine kinase 3 (FLT3). Besides PDGFR and FLT3, crenolanib does not inhibit any other known receptor tyrosine kinase (RTK) (e.g. VEGFR and FGFR) or any other serine/threonine kinase (e.g., Abl, Raf) at clinically achievable concentrations.

The important aspect about the constitutively active point mutations of FLT3 (D835V/Y) and the analogous mutation in PDGFRA (D842V) and c-KIT (D816V) is that they are resistant to both FDA approved and clinical development stage tyrosine kinase inhibitors (TKIs). The acquisition of these point mutations in the FLT3 (ITD and TKD), PDGFRA, and c-Kit genes were shown to induce constitutive activation of the receptor- and ligand-independent cell growth in different cell lines. These mutations are hypersensitive to crenolanib. The table below provides a summary of the potency of crenolanib for inhibiting these constitutively activating mutations of Type III receptor kinases PDGFRA and FLT3.

Crenolanib

crenolanib2