Smoothened (hedgehog pathway)
The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.
Hedgehog ligand binding to PTCH1 releases SMO, a GPCR-like protein, to activate GLI transcription factors. PTCH1 loss (~70%) or SMO mutation (~10-20%) drives essentially all basal cell carcinoma, SHH-subgroup medulloblastoma (~30%) and Gorlin syndrome. Vismodegib (2012) and sonidegib (2015) treat advanced BCC; glasdegib (2018) with low-dose cytarabine treats unfit AML. Class toxicities (muscle spasms, dysgeusia, alopecia, teratogenicity) limit duration; SMO mutations (D473H, W535L) cause resistance; downstream GLI or SUFU-loss tumours do not respond.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.
- 1 · What it is
The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.
- 2 · What goes wrong in cancer
Seven-transmembrane Frizzled-class receptor; cholesterol binding to its cysteine-rich domain and transmembrane site activates it once PTCH1 inhibition is relieved, translocating to the primary cilium and derepressing GLI2/3.
- 3 · How drugs use it
3 products aim at Smoothened (hedgehog pathway): small molecules. Drugs bind the molecule precisely: to switch it off, flag the cell for the immune system, or deliver a payload.
Biology
Seven-transmembrane Frizzled-class receptor; cholesterol binding to its cysteine-rich domain and transmembrane site activates it once PTCH1 inhibition is relieved, translocating to the primary cilium and derepressing GLI2/3.
- Basal cell carcinoma (PTCH1 ~70%, SMO ~10-20%)
- SHH medulloblastoma (~30% of medulloblastoma)
- Gorlin syndrome (germline PTCH1/SUFU)
- AML (pathway activity in leukaemic stem cells)
How common it is, by cancer
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Basal cell carcinoma | 85% | hedgehog pathway activation (PTCH1 or SMO) | doi.org | |
| Medulloblastoma | 30% | SHH subgroup |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Glasdegib is a hedgehog-pathway pill that, with low-dose chemotherapy, extends survival in older AML patients who cannot have intensive treatment; it has largely been displaced by venetoclax combinations.
Sonidegib (Odomzo) is the second hedgehog inhibitor for locally advanced basal cell carcinoma, similar in effect and side effects to vismodegib.
Vismodegib was the first hedgehog-pathway drug, for basal cell carcinomas too advanced for surgery; it shrinks most tumours but muscle cramps, taste loss and hair loss make long-term use hard.
Latest papers
topQuery for this target: (TITLE:"Smoothened" OR ABSTRACT:"Smoothened" OR TITLE:"hedgehog pathway" OR ABSTRACT:"hedgehog pathway" OR TITLE:"SMO" OR ABSTRACT:"SMO") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Smoothened (hedgehog pathway), not a curated reading list.
Pages like this
not linked directly; found by shared links- ProductRuxolitinib
Shares Fibroblast activation, desmoplasia & matrix stiffness, Small-molecule kinase inhibitors and the tag gap-fill.
- TargetJAK2
Shares Fibroblast activation, desmoplasia & matrix stiffness, Small-molecule kinase inhibitors and the tag gap-fill.
- TargetMDM2
Shares Acute myeloid leukaemia, Small-molecule kinase inhibitors and the tag gap-fill.
- ProductEnsartinib
Shares Small-molecule kinase inhibitors and the tag gap-fill.
- ProductDacomitinib
Shares Small-molecule kinase inhibitors and the tag gap-fill.
- ProductCeritinib
Shares Small-molecule kinase inhibitors and the tag gap-fill.
- ProductBrigatinib
Shares Small-molecule kinase inhibitors and the tag gap-fill.
- ProductTaletrectinib
Shares Small-molecule kinase inhibitors and the tag gap-fill.