Crenolanib (CP-868-596)

Next Generation Inhibitor of Receptor Tyrosine Kinases

  • Unique chemo-type with benzimidazole backbone
  • Preferentially inhibits phosphorylated receptors
  • Activity against wild type & 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.


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

  • Dose range: 100mg QD to 340mg QD
  • Most AEs were grade 1 or 2
  • Only grade 3 or 4 AEs were
  •  Nausea/vomiting
  • Reversible liver enzyme elevations

Phase Ib trial (combination), Michael M, et al. 2010

  • Combination with full doses of docetaxel axitinib
  • Safely combined with non-overlapping PK profile

There are three ongoing clinical trials of crenolanib in the US:

  1. A Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas (NCT01229644)
  2. A Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of GIST (NCT01243346)
  3. Phase I Study of Platelet Derived Growth Factor Receptor (PDGFR) Inhibitor, Crenolanib in Newly Diagnosed and Recurrent High-grade Pediatric Glioma Including Diffuse Intrinsic Pontine Glioma (NCT01393912)

The anticipated trials of crenolanib include Phase II trials in:

  • Acute Myeloid Leukemia
  • Ovarian Cancer