Sonidegib

Summary

Sonidegib (CHEMBL2105737) is an approved small-molecule antineoplastic agent (ATC L01XJ02) targeting SMO; indicated across 15 conditions including neoplasm and breast neoplasm; with CIViC clinical evidence for 7 variant-indication associations (e.g. PTCH1 Loss-of-function in basal cell carcinoma).

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: L01XJ02
• Targets: 1 (SMO)
• Indications: 15 conditions
• Clinical trials: 41
• Precision-oncology evidence (CIViC): 7 variant–indication associations
• Chemistry: 485.5 Da · C26H26F3N3O3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL2105737
Name	Sonidegib
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	24775005
ChEBI	CHEBI:90863
ATC	L01XJ02
Molecular formula	C26H26F3N3O3
Molecular weight	485.5
InChIKey	VZZJRYRQSPEMTK-CALCHBBNSA-N

SMILES: C[C@@H]1CN(C[C@@H](O1)C)C2=NC=C(C=C2)NC(=O)C3=CC=CC(=C3C)C4=CC=C(C=C4)OC(F)(F)F

IUPAC name: N-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3-pyridinyl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide

ChEBI definition: A member of the classo of biphenyls that is the amide obtained by formal condensation of the carboxy group of 2-methyl-4’-(trifluoromethoxy)[1,1’-biphenyl]-3-carboxylic acid with the amino group of 6-(2,6-dimethylmorpholin-4-yl)pyridin-3-amine. Used (as its phosphate salt) for treatment of locally advanced basal cell carcinoma.

Pharmacological roles (ChEBI): antineoplastic agent, SMO receptor antagonist, Hedgehog signaling pathway inhibitor.

Also known as: Erismodegib, LDE 225, LDE-225, LDE225, NVP-LDE 225, NVP-LDE-225, NVP-LDE225, Sonidegib, SONIDEGIB, sonidegib, LDE225 (NVP-LDE225, ERISMODEGIB), Sonidegib phosphateÊ

Parent form; salt/anhydrous children: CHEMBL3137317

Patent coverage: 1,590 distinct patent families (3,859 SureChEMBL compound mentions), from 1 matched compound structure(s). Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
SMO	SMO	Antagonist	8.22		Q99835

Broader ChEMBL bioactivity targets: 4 (assay-derived). Sample: Progesterone receptor, G-protein coupled receptor 183, Sonic hedgehog protein, Protein smoothened.

Bioactivity

ChEMBL activities: 3 potent at pChembl ≥ 5 of 4 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
Q62226	8.26	IC50	5.5	nM	CHEMBL_ACT_13843839
SMO	8.22	Ki	6	nM	CHEMBL_ACT_12076103
GPR183	5.5	IC50	3174	nM	CHEMBL_ACT_25751448

Target pathways

Aggregated over 1 target gene(s): SMO.

Top Reactome pathways

12 total, by targets touching each:

Pathway	Targets	Genes
Signal Transduction	1	SMO
Organelle biogenesis and maintenance	1	SMO
Signaling by GPCR	1	SMO
Class B/2 (Secretin family receptors)	1	SMO
GPCR ligand binding	1	SMO
Signaling by Hedgehog	1	SMO
Hedgehog ‘off’ state	1	SMO
Cilium Assembly	1	SMO
Cargo trafficking to the periciliary membrane	1	SMO
BBSome-mediated cargo-targeting to cilium	1	SMO
Hedgehog ‘on’ state	1	SMO
Activation of SMO	1	SMO

Dominant GO biological processes

GO term	Targets
negative regulation of transcription by RNA polymerase II	1
vasculogenesis	1
osteoblast differentiation	1
in utero embryonic development	1
cell fate specification	1
neural crest cell migration	1
negative regulation of protein phosphorylation	1
heart looping	1
positive regulation of neuroblast proliferation	1
positive regulation of mesenchymal cell proliferation	1
determination of left/right asymmetry in lateral mesoderm	1
type B pancreatic cell development	1
protein import into nucleus	1
apoptotic process	1
smoothened signaling pathway	1

Indications & clinical

Indications

15 indications (1 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
neoplasm	4	MONDO:0005070	EFO:0000616
breast neoplasm	2	MONDO:0021100	EFO:0003869
medulloblastoma	2	MONDO:0007959	EFO:0002939
basal cell carcinoma	2	MONDO:0020804	EFO:0004193
leukemia	2	MONDO:0005059	EFO:0000565
plasma cell myeloma	2	MONDO:0009693	EFO:0001378
liver disorder	1	MONDO:0005154	EFO:0001421
exocrine pancreatic carcinoma	1	MONDO:0005192	EFO:0002618
ovarian cancer	1	MONDO:0008170	MONDO:0008170
graft versus host disease	1	MONDO:0013730	MONDO:0013730
hepatocellular carcinoma	1	MONDO:0007256	EFO:0000182

4 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 41.

Phase distribution

Phase	Trials
PHASE1	18
PHASE2	15
Not specified	5
PHASE1/PHASE2	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05669339	PHASE2	RECRUITING	AD HOC Trial: Artificial Intelligence-Based Drug Dosing In Hepatocellular Carcinoma
NCT00961896	PHASE2	COMPLETED	A Trial to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of LDE225 on Skin Basal Cell Carcinomas in Gorlin Syndrome Patients
NCT01033019	PHASE2	TERMINATED	To Evaluate the Safety, Local Tolerability, PK and PD of LDE225 on Sporadic Superficial and Nodular Skin Basal Cell Carcinomas (sBCC)
NCT01125800	PHASE1/PHASE2	COMPLETED	A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB
NCT01327053	PHASE2	COMPLETED	A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma
NCT01350115	PHASE2	COMPLETED	Efficacy, Safety and Pharmacokinetics of Oral LDE225 in Treatment of Patients With Nevoid Basal Cell Carcinoma Syndrome (NBCCS)
NCT01708174	PHASE2	COMPLETED	A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)
NCT01757327	PHASE2	WITHDRAWN	LDE225 in Treating Patients With Stage II-III Estrogen Receptor- and HER2-Negative Breast Cancer
NCT01787552	PHASE1/PHASE2	COMPLETED	A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF
NCT01826214	PHASE2	COMPLETED	Study of Efficacy and Safety of LDE225 in Adult Patients With Relapsed/Refractory Acute Leukemia
NCT02002689	PHASE2	TERMINATED	LDE225 for Patients With PTCH1 or SMO Mutated Tumors
NCT02086552	PHASE2	COMPLETED	Sonidegib and Lenalidomide After Stem Cell Transplant in Treating Patients With Multiple Myeloma
NCT02254551	PHASE2	TERMINATED	Safety/Efficacy Study of LDE225 (Sonidegib) Plus Bortezomib in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma
NCT02303041	PHASE2	TERMINATED	Pilot Study of Sonidegib and Buparlisib in Treating Patients With Advanced or Metastatic Basal Cell Carcinoma
NCT03534947	PHASE2	COMPLETED	A Study to Evaluate Neoadjuvant Sonidegib Followed by Surgery or Imiquimod in the Management of Basal Cell Carcinoma
NCT04402073	PHASE2	TERMINATED	Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma
NCT04806646	PHASE2	UNKNOWN	Tailored Sonidegib Schedule After Complete Response in BCC
NCT04007744	PHASE1	ACTIVE_NOT_RECRUITING	Sonidegib and Pembrolizumab in Treating Patients With Advanced Solid Tumors
NCT00880308	PHASE1	COMPLETED	Dose Finding and Safety of Oral LDE225 in Patients With Advanced Solid Tumors
NCT01208831	PHASE1	COMPLETED	An East Asian Study of LDE225
NCT01456676	PHASE1	COMPLETED	Nilotinib and LDE225 in the Treatment of Chronic or Accelerated Phase Myeloid Leukemia in Patients Who Developed Resistance to Prior Therapy
NCT01487785	PHASE1	COMPLETED	Dose-escalation, and Safety Study of LDE225 and Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer Patients
NCT01576666	PHASE1	COMPLETED	Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors
NCT01764776	PHASE1	COMPLETED	Effect of Hepatic Impairment on LDE225..
NCT01769768	PHASE1	COMPLETED	Phase I Study to Evaluate the Effect of LDE225 on the Pharmacokinetics of Bupropion and Warfarin in Patients
NCT01954355	PHASE1	COMPLETED	LDE225 and Paclitaxel in Solid Tumors
NCT02027376	PHASE1	COMPLETED	Study of LDE225 (Sonidegib) in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients
NCT02086513	PHASE1	TERMINATED	Phase I Trial of LDE225 for Steroid-refractory Chronic GVHD After Allogeneic HSCT
NCT02111187	PHASE1	COMPLETED	A Pre-surgical Study of LDE225 in Men With High-risk Localized Prostate Cancer
NCT02129101	PHASE1	COMPLETED	Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies
NCT02138929	PHASE1	COMPLETED	LDE225 + Everolimus in Advanced Gastroesophageal Adenocarcinoma
NCT02151864	PHASE1	COMPLETED	LDE225 in Patients With Advanced or Metastatic Hepatocellular Carcinoma and Child-Pugh A/B7 Cirrhosis
NCT02182622	PHASE1	WITHDRAWN	LDE225 + Docetaxel/Prednisone for Adv/Met Castrate Resistant Prostate Cancer w/ Disease Progression After Docetaxel
NCT02195973	PHASE1	COMPLETED	Phase IB Trial of LDE225 and Paclitaxel in Recurrent Ovarian Cancer
NCT03434262	PHASE1	COMPLETED	SJDAWN: St. Jude Children’s Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors
NCT01694589	EARLY_PHASE1	WITHDRAWN	A Pilot Study of a Hedgehog Pathway Inhibitor (LDE-225) in Surgically Resectable Pancreas Cancer
NCT05463757	Not specified	RECRUITING	Oral Hedgehog Inhibitors in the Treatment of Basal Cell Carcinoma in the Netherlands: a Prospective Registration Study
NCT01529450	Not specified	COMPLETED	Pilot LDE225 in Locally Advanced or Metastatic BCC + Previously Tx Non-LDE225 Smoothened Inhibitors
NCT01911416	Not specified	WITHDRAWN	A Biomarker Study to Identify Predictive Signatures of Response to LDE225 (Hedgehog Inhibitor) In Patients With Resectable Pancreatic Cancer
NCT04066504	Not specified	COMPLETED	Post-authorization Safety Study on the Long Term Safety of Sonidegib in Patients With Locally Advanced Cell Carcinoma

Clinical evidence (CIViC)

Variant × indication × effect (7 predictive associations from 7 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
PTCH1 Loss-of-function	Basal Cell Carcinoma	Sensitivity/Response	Sonidegib	CIViC A	EID11608
PTCH1 Mutation	Medulloblastoma	Sensitivity/Response	Sonidegib	CIViC B	EID748
SMO Mutation	Basal Cell Carcinoma	Resistance	Vismodegib + Sonidegib	CIViC B	EID1477
PTCH1 Deletion	Medulloblastoma	Sensitivity/Response	Sonidegib	CIViC D	EID5326
SMO Amplification	Lung Non-small Cell Carcinoma	Sensitivity/Response	Sonidegib + Gefitinib	CIViC D	EID2946
MYCN Amplification	Medulloblastoma	Resistance	Sonidegib	CIViC D	EID5325
SUFU Deletion	Medulloblastoma	Resistance	Sonidegib	CIViC D	EID5324

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

10 molecules share ≥1 primary target. Top 10 by shared-target count:

Molecule	Source	Status	Shared targets
INFIGRATINIB	ChEMBL + PubChem	Phase 4 (approved)	SMO
VISMODEGIB	ChEMBL + PubChem	Phase 4 (approved)	SMO
LINIFANIB	ChEMBL	Phase 3	SMO
PATIDEGIB	ChEMBL	Phase 3	SMO
CEP-32496	ChEMBL	Phase 2	SMO
FORETINIB	ChEMBL	Phase 2	SMO
TALADEGIB	ChEMBL	Phase 2	SMO
cholecalciferol	PubChem	Approved	SMO
Ergocalciferol	PubChem	Approved	SMO
Glasdegib	PubChem	Approved	SMO