Lymphangioleiomyomatosis

Summary

Lymphangioleiomyomatosis (MONDO:0011705) is a disease caused by TSC2 (GenCC Strong), with 7 cohort genes (1 GWAS associations across 1 studies) and 44 clinical trials. Top therapeutic interventions include doxycycline anhydrous, glutamine, and loratadine.

At a glance

• Causal gene: TSC2 (GenCC Strong)
• Cohort genes: 7
• GWAS associations: 1
• ClinVar variants: 880
• Clinical trials: 44

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphangioleiomyomatosis
Mondo ID	MONDO:0011705
MeSH	D018192
OMIM	606690
ICD-10-CM	J84.81
ICD-11	902628446
NCIT	C3725
UMLS	C0751674
MedGen	148366
GARD	0024820
Is cancer (heuristic)	no

Also known as: LAM · lung lymphangioleiomyomatosis · lymphangio-myomatosis · lymphangioleiomyomatosis · lymphangioleiomyomatosis, somatic · lymphangiomyomatosis · pulmonary lymphangioleiomyomatosis

Data availability: 880 ClinVar variants · 1 GWAS association (1 study) · 1 GenCC gene-disease record · 23 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › connective and soft tissue neoplasm › soft tissue neoplasm › neoplasm with perivascular epithelioid cell differentiation › lymphangioleiomyomatosis

Related subtypes (5): angiomyolipoma, uterine corpus perivascular epithelioid cell tumor, lymphangiomyoma, benign PEComa, lung PEComa

Subtypes (1): lung lymphangioleiomyomatosis

Genetics & variants

GWAS landscape

1 GWAS associations across 1 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2006950	3e-08	LINC00924 - RNU2-3P	G	2.4

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST008311	Kim W	2019	426	0	A Genome-Wide Association Study implicates NR2F2 in Lymphangioleiomyomatosis Pathogenesis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2006950	15	95636161	G>A	0.238	intron_variant	LINC00924 - RNU2-3P	3e-08	Tier 4: intronic/intergenic

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

185 conflicting classifications of pathogenicity, 150 benign/likely benign, 138 uncertain significance, 55 pathogenic, 27 likely benign, 17 pathogenic/likely pathogenic, 12 benign, 9 likely pathogenic, 7 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3892957	NC_000016.9:g.(?2120457)(2185690_?)del	MIR1225	Pathogenic	criteria provided, single submitter
3382611	NM_000368.5(TSC1):c.741G>A (p.Trp247Ter)	TSC1	Pathogenic	criteria provided, single submitter
3780751	NM_000368.5(TSC1):c.363+668G>A	TSC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
421669	NM_000368.5(TSC1):c.1326_1327del (p.Gly443fs)	TSC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48729	NM_000368.5(TSC1):c.1029+1G>A	TSC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48779	NM_000368.5(TSC1):c.1431_1434del (p.Glu478fs)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
48791	NM_000368.5(TSC1):c.1498C>T (p.Arg500Ter)	TSC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48796	NM_000368.5(TSC1):c.1525C>T (p.Arg509Ter)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
48885	NM_000368.5(TSC1):c.2074C>T (p.Arg692Ter)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
48886	NM_000368.5(TSC1):c.2082del (p.Gln694fs)	TSC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48902	NM_000368.5(TSC1):c.211-1G>A	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
48941	NM_000368.5(TSC1):c.2341C>T (p.Gln781Ter)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
48943	NM_000368.5(TSC1):c.2356C>T (p.Arg786Ter)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
48971	NM_000368.5(TSC1):c.2509_2512del (p.Asn837fs)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
49046	NM_000368.5(TSC1):c.491G>A (p.Trp164Ter)	TSC1	Pathogenic	criteria provided, single submitter
49083	NM_000368.5(TSC1):c.682C>T (p.Arg228Ter)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
49118	NM_000368.5(TSC1):c.891T>G (p.Tyr297Ter)	TSC1	Pathogenic	criteria provided, single submitter
12393	NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12396	NM_000548.5(TSC2):c.1513C>T (p.Arg505Ter)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12397	NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12400	NM_000548.5(TSC2):c.1096G>T (p.Glu366Ter)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12402	NM_000548.5(TSC2):c.5238_5255del (p.His1746_Arg1751del)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12403	NM_000548.5(TSC2):c.2714G>A (p.Arg905Gln)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12404	NM_000548.5(TSC2):c.2713C>T (p.Arg905Trp)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1686276	NM_000548.5(TSC2):c.595del (p.Val199fs)	TSC2	Pathogenic	criteria provided, single submitter
1686277	NM_000548.5(TSC2):c.1380_1386del (p.Val461fs)	TSC2	Pathogenic	criteria provided, single submitter
1686278	NM_000548.5(TSC2):c.3040dup (p.Ser1014fs)	TSC2	Pathogenic	criteria provided, single submitter
1686279	NM_000548.5(TSC2):c.3376del (p.Asp1126fs)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1686280	NM_000548.5(TSC2):c.4279dup (p.Ser1427fs)	TSC2	Pathogenic	criteria provided, single submitter
1810234	NM_000548.5(TSC2):c.1528C>T (p.Gln510Ter)	TSC2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 17 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TSC2	Strong	Autosomal dominant	lymphangioleiomyomatosis	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
TSC1	Orphanet:210159	Adult hepatocellular carcinoma
TSC1	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC1	Orphanet:538	Lymphangioleiomyomatosis
TSC1	Orphanet:805	Tuberous sclerosis complex
NR2F2	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
NR2F2	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot
NTHL1	Orphanet:454840	NTHL1-related polyposis
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	1
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	gencc,clinvar
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	clinvar
MIR1225	HGNC:33931	ENSG00000221656		microRNA 1225	clinvar
NR2F2	HGNC:7976	ENSG00000185551	P24468	COUP transcription factor 2	gwas
NTHL1	HGNC:8028	ENSG00000065057	P78549	Endonuclease III-like protein 1	clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
TSC1	Hamartin	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
NR2F2	COUP transcription factor 2	Ligand-activated transcription factor.
NTHL1	Endonuclease III-like protein 1	Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.57

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	55.1×	0.090
Antibody/Immunoglobulin	1	4.2×	0.378
Kinase	1	4.0×	0.378
Enzyme (other)	1	1.7×	0.571
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
TSC1	Other/Unknown	no		Hamartin
MIR1225	Other/Unknown	no
NR2F2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
NTHL1	Enzyme (other)	yes	4.2.99.18	HhH_motif, HhH-GPD_domain, Endonuclease3_FeS-loop_motif
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
gluteal muscle	1
lateral globus pallidus	1
substantia nigra pars compacta	1
Brodmann (1909) area 9	1
skeletal muscle tissue	1
sural nerve	1
cardia of stomach	1
dorsal root ganglion	1
urethra	1
apex of heart	1
mucosa of transverse colon	1
right lobe of liver	1
seminal vesicle	1
thoracic aorta	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
MIR1225	77		yes	sural nerve, skeletal muscle tissue, Brodmann (1909) area 9
NR2F2	289	ubiquitous	marker	urethra, cardia of stomach, dorsal root ganglion
NTHL1	211	ubiquitous	marker	right lobe of liver, apex of heart, mucosa of transverse colon
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSC1	5,445
TSC2	4,135
NR2F2	2,741
PRKD1	2,131
NTHL1	1,994
PKD1	1,370
MIR1225	0

Intra-cohort edges

A	B	Sources
PKD1	PRKD1	string_interaction
PKD1	TSC1	string_interaction
PKD1	TSC2	string_interaction
TSC1	TSC2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PKD1	P98161	13
TSC1	Q92574	5
TSC2	P49815	2
NTHL1	P78549	2
NR2F2	P24468	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKD1	Q15139	68.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 7 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inhibition of TSC complex formation by AKT (PKB)	2	761.3×	4e-05	TSC2, TSC1
Energy dependent regulation of mTOR by LKB1-AMPK	2	131.3×	9e-04	TSC2, TSC1
TBC/RABGAPs	2	86.5×	0.001	TSC2, TSC1
Defective NTHL1 substrate processing	1	1903.3×	0.002	NTHL1
Defective NTHL1 substrate binding	1	1903.3×	0.002	NTHL1
TP53 Regulates Metabolic Genes	2	43.3×	0.003	TSC2, TSC1
Macroautophagy	2	38.5×	0.003	TSC2, TSC1
Displacement of DNA glycosylase by APEX1	1	173.0×	0.014	NTHL1
AKT phosphorylates targets in the cytosol	1	135.9×	0.015	TSC2
VxPx cargo-targeting to cilium	1	86.5×	0.022	PKD1
Constitutive Signaling by AKT1 E17K in Cancer	1	70.5×	0.024	TSC2
Sphingolipid de novo biosynthesis	1	47.6×	0.033	PRKD1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	30.7×	0.044	NTHL1
Cleavage of the damaged pyrimidine	1	30.7×	0.044	NTHL1
Sphingolipid metabolism	1	28.0×	0.045	PRKD1
Transcriptional regulation of white adipocyte differentiation	1	21.6×	0.052	NR2F2
Interaction of NuRD complexes with transcription factors	1	21.1×	0.052	NR2F2
Metabolism of lipids	1	5.3×	0.186	PRKD1
Metabolism	1	1.9×	0.417	PRKD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
placenta blood vessel development	2	468.1×	0.001	NR2F2, PKD1
negative regulation of TOR signaling	2	187.2×	0.002	TSC2, TSC1
regulation of cell cycle	3	37.3×	0.002	TSC2, TSC1, PKD1
negative regulation of TORC1 signaling	2	108.0×	0.005	TSC2, TSC1
radial pattern formation	1	2808.7×	0.008	NR2F2
metanephric distal tubule morphogenesis	1	2808.7×	0.008	PKD1
cellular response to starvation	2	64.6×	0.008	TSC2, TSC1
neural tube closure	2	62.4×	0.008	TSC2, TSC1
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	1404.3×	0.009	PRKD1
nitrogen cycle metabolic process	1	1404.3×	0.009	PKD1
mesonephric tubule development	1	1404.3×	0.009	PKD1
cell-matrix adhesion	2	54.5×	0.009	TSC1, PKD1
kidney development	2	46.8×	0.009	TSC1, PKD1
lymph vessel morphogenesis	1	936.2×	0.010	PKD1
memory T cell differentiation	1	936.2×	0.010	TSC1
lymphatic endothelial cell fate commitment	1	936.2×	0.010	NR2F2
metanephric proximal tubule development	1	936.2×	0.010	PKD1
calcium-independent cell-matrix adhesion	1	702.2×	0.011	PKD1
cellular response to decreased oxygen levels	1	702.2×	0.011	TSC1
cellular response to norepinephrine stimulus	1	702.2×	0.011	PRKD1
metanephric ascending thin limb development	1	702.2×	0.011	PKD1
base-excision repair, AP site formation	1	561.7×	0.012	NTHL1
mesonephric duct development	1	561.7×	0.012	PKD1
positive regulation of sarcomere organization	1	468.1×	0.013	PRKD1
mitocytosis	1	468.1×	0.013	PKD1
heart development	2	26.2×	0.014	TSC2, PKD1
lung epithelium development	1	351.1×	0.015	PKD1
cellular response to hydroperoxide	1	351.1×	0.015	PRKD1
regulation of integrin-mediated signaling pathway	1	351.1×	0.015	PRKD1
response to fluid shear stress	1	312.1×	0.015	PKD1

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Sirolimus	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Celecoxib, Everolimus, Letrozole, Loratadine, Nintedanib, Resveratrol, Saracatinib.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 5 of 7 evidence-associated genes (71%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
NR2F2	3	3
TSC2	0	0
TSC1	0	0
MIR1225	0	0
NTHL1	0	0
PKD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
CARBOXYAMIDOTRIAZOLE	3	NR2F2
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
CYCLOHEXIMIDE	2	NR2F2
CHLORMIDAZOLE	2	NR2F2
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
PKD1	27	Binding:27
NTHL1	8	Binding:7, Functional:1
NR2F2	2	Binding:1, Functional:1
TSC2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NTHL1	4.2.99.18	DNA-(apurinic or apyrimidinic site) lyase
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

28 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
CARBOXYAMIDOTRIAZOLE	3	NR2F2
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
CYCLOHEXIMIDE	2	NR2F2
CHLORMIDAZOLE	2	NR2F2
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKD1
B	Phased (≥1) drug, not yet approved	1	NR2F2
C	Druggable family + PDB, no drug	2	NTHL1, PKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TSC2, TSC1, MIR1225

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
TSC2	1	—
TSC1	0	—
MIR1225	0	—
NTHL1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 44.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	18
PHASE2	11
PHASE1/PHASE2	5
PHASE1	5
PHASE3	3
PHASE4	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00989742	PHASE4	COMPLETED	Doxycycline In Lymphangioleiomyomatosis (LAM)
NCT03150914	PHASE3	ACTIVE_NOT_RECRUITING	Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial
NCT00414648	PHASE3	COMPLETED	Efficacy and Safety of Sirolimus in LAM
NCT00790400	PHASE3	COMPLETED	Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
NCT01799538	PHASE1/PHASE2	RECRUITING	Nebulized or Inhaled Albuterol for Lymphangioleiomyomatosis
NCT05467397	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Feasibility of [11C]Acetate-PET in LAM and TSC
NCT00005906	PHASE2	COMPLETED	Treatment With Octreotide in Patients With Lymphangioleiomyomatosis
NCT00457808	PHASE2	COMPLETED	Rapamycin Therapy for Patients With Tuberous Sclerosis Complex and Sporadic LAM
NCT00457964	PHASE1/PHASE2	COMPLETED	RAD001 Therapy of Angiomyolipomata in Patients With TS Complex and Sporadic LAM
NCT00490789	PHASE2	UNKNOWN	Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM
NCT01059318	PHASE2	COMPLETED	A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis
NCT01353209	PHASE2	COMPLETED	Letrozole for Lymphangioleiomyomatosis
NCT02061397	PHASE1/PHASE2	COMPLETED	Safety of Simvastatin in LAM and TSC
NCT02484664	PHASE2	COMPLETED	COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC
NCT02737202	PHASE2	TERMINATED	Safety and Efficacy of Saracatinib In Subjects With Lymphangioleiomyomatosis
NCT03062943	PHASE2	COMPLETED	A Study of Nintedanib for LymphAngioleioMyomatosis (LAM)
NCT03131999	PHASE1/PHASE2	COMPLETED	LAM Pilot Study With Imatinib Mesylate
NCT03253913	PHASE2	COMPLETED	Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial
NCT03304678	PHASE2	COMPLETED	Discovery of Sirolimus Sensitive Biomarkers in Blood
NCT05190627	PHASE2	UNKNOWN	Effect of Loratadine in Lymphangioleiomyomatosis
NCT06889168	PHASE1	RECRUITING	Evaluating the Long-term Safety and Tolerability of Imatinib in Patients With Lymphangioleiomyomatosis (LAM)
NCT01552434	PHASE1	TERMINATED	Bevacizumab and Temsirolimus Alone or in Combination With Valproic Acid or Cetuximab in Treating Patients With Advanced or Metastatic Malignancy or Other Benign Disease
NCT01687179	PHASE1	COMPLETED	Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis
NCT02116712	PHASE1	COMPLETED	The Tolerability of Saracatinib in Subjects With Lymphangioleiomyomatosis (LAM) (SLAM-1)
NCT04388371	PHASE1	COMPLETED	Glutamine PET Imaging in LAM
NCT05087134	EARLY_PHASE1	UNKNOWN	Characterizing LAM With 11C-Choline PET/CT
NCT00001465	Not specified	RECRUITING	Study of the Disease Process of Lymphangioleiomyomatosis
NCT01484236	Not specified	RECRUITING	National Lymphangioleiomyomatosis Registry, France
NCT02432560	Not specified	RECRUITING	Safety and Durability of Sirolimus for Treatment of LAM
NCT05676099	Not specified	RECRUITING	TSC Biosample Repository and Natural History Database
NCT05727852	Not specified	ENROLLING_BY_INVITATION	Breath Analysis and Arterial Stiffness in Patients With Respiratory Diseases
NCT06160310	Not specified	RECRUITING	Tuberous Sclerosis Complex and Lymphangioleiomyomatosis Pregnancy Registry (TSC-LAM Registry)
NCT07304856	Not specified	RECRUITING	Role of Extracellular Vesicles as Biomarkers of Pulmonary Involvement in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex
NCT00005486	Not specified	COMPLETED	Lymphangioleiomyomatosis (LAM) Registry
NCT00366509	Not specified	COMPLETED	Role of Helicobacter Pylori and Its Toxins in Lung and Digestive System Diseases
NCT00552955	Not specified	COMPLETED	Effect of Fasting on the Size of Abdominal Lymphatic Tumors in Women
NCT00960895	Not specified	COMPLETED	Pulmonary Hypertension in Lymphangioleiomyomatosis
NCT02009241	Not specified	COMPLETED	Pulmonary Rehabilitation in Lymphangioleiomyomatosis
NCT02325505	Not specified	COMPLETED	Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma
NCT02654340	Not specified	TERMINATED	Biomarkers for Tuberous Sclerosis Complex (BioTuScCom)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DOXYCYCLINE ANHYDROUS	4	3
GLUTAMINE	4	1
LORATADINE	4	1
NINTEDANIB	4	1
OCTREOTIDE	4	1
SIROLIMUS	4	1
SARACATINIB	3	2
RESVERATROL	3	1
CHEMBL4438584	0	2
CHEMBL3350037	0	1