Next Generation Inhibitor of Receptor Tyrosine Kinases
The chemical name of crenolanib besylate is 4-piperidinamine, 1-[2-[5-[(3-Methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-, monobenzenesulfonate.
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 the FMS-related tyrosine kinase 3 (FLT3). Besides PDGFR and Flt3, crenolanib does not inhibit any other know RTK (VEGFR, FGFR) or any other serine/threonine kinase (abl, raf) at clinically achievable concentrations
The important aspect about the constitutively active point mutations of FLT3 (D835V/Y) and its analogous mutation in PDGFRA (D842V) and c-KIT (D816V) are that they are resistant to both FDA approved and clinical developmental stage TKIs. The acquisition of these point mutations in the FLT3 (ITD and TKD), PDGFRA, and c-Kit gene was shown to induce constitutive activation of the receptor- and ligand-independent cell growth in different cell lines. These mutations are hyper-sensitive to crenolanib. 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 has been clinically evaluated in the Phase I setting as a single agent and in the Phase Ib setting in combination with docetaxel and axitinib.
Phase I trial (single agent), Lewis N, et al. 2009
Phase Ib trial (combination), Michael M, et al. 2010
There are three ongoing clinical trials of crenolanib in the US:
The anticipated trials of crenolanib include Phase II trials in: