Glasdegib is an orally bioavailable Smoothened (SMO) inhibitor developed by Pfizer to suppress Hedgehog signaling. Its clinical development led to FDA approval in 2018 with low-dose cytarabine for newly diagnosed acute myeloid leukemia (AML) in adults aged 75 or older, or with comorbidities precluding intensive induction chemotherapy.
The Glasdegib chemical structure corresponds to the free-base formula C21H22N6O and a molecular weight of 374.44 g/mol. Salt forms have different compositions and must be distinguished from this neutral molecule.
Application of Glasdegib
Researchers use the compound to investigate SMO-dependent signaling in leukemia stem cells, Hedgehog-driven tumors and combination studies with cytotoxic agents. Measuring GLI expression alongside proliferation or clonogenic growth helps distinguish pathway inhibition from a broader reduction in cell viability.
Because Glasdegib is not spirocyclic, it also provides a benzimidazole-based comparator for SMO inhibitors built on spirocyclic cores. Structural differences alone, however, do not establish differences in cellular selectivity.
In Vitro
PF-04449913 showed an IC50 of 4 nM in a human SMO ligand-displacement assay. This measures competition for binding; pathway-reporter and leukemia-cell assays evaluate different downstream responses.
The Hedgehog inhibitor PF-04449913 reduced clonogenic growth of primary AML cells in replating experiments, with a negligible effect on cord-blood colony formation under the tested conditions. Such comparisons are model-specific and do not establish universal sparing of normal stem cells.
In Vivo
In mice engrafted with human blast-crisis leukemia stem cells, daily treatment reduced spleen weight and GLI2 protein expression. These findings linked reduced leukemic burden with a pathway readout.
The Pfizer Glasdegib clinical program also included a randomized Phase 2 trial in AML or high-risk myelodysplastic syndrome. With low-dose cytarabine, complete remission was 17.0% versus 2.3% with cytarabine alone; median overall survival was 8.8 versus 4.9 months.
Biochemical and Physiological Actions
The Glasdegib molecular structure links a benzimidazole to an N-methylpiperidine bearing a cyanophenyl urea group. The molecule inhibits SMO, rather than binding directly to GLI transcription factors.
Without Hedgehog ligand, PTCH1 represses SMO. Ligand binding to PTCH1 releases this inhibition, allowing GLI-dependent transcription. SMO antagonism interrupts this signal, but downstream pathway regulation can affect sensitivity. In AML models, GLI3 repressor status was associated with response to treatment.
Features and Benefits of Glasdegib
The Glasdegib structure has defined (2R,4R) stereochemistry, supporting comparison with the compound characterized in discovery studies. Published binding, cellular and animal results provide distinct reference endpoints for experimental design.
CAS 1095173-27-5 identifies the free base. Confirm the salt form, stereochemical identity and batch documentation before preparing stock solutions. Solubility and formulation data should match the supplied form rather than a different salt or supplier preparation.
Powered by Bioz