Shigellosis

Summary

Shigellosis (MONDO:0019345) is a disease with 8 cohort genes (12 GWAS associations across 1 studies) and 24 clinical trials. Top therapeutic interventions include azithromycin, ceftriaxone, and ciprofloxacin.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 8
• GWAS associations: 12
• Phenotypes (HPO): 46
• Clinical trials: 24

Clinical features

Epidemiology

Prevalence records

29 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1.68	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.78	Austria	Validated
Annual incidence	1-9 / 100 000	8.18	Bulgaria	Validated
Annual incidence	1-9 / 1 000 000	0.33	Croatia	Validated
Annual incidence	<1 / 1 000 000	0.04	Cyprus	Validated
Annual incidence	1-9 / 100 000	1.6	Czech Republic	Validated
Annual incidence	1-9 / 100 000	2.08	Denmark	Validated
Annual incidence	1-9 / 100 000	1.38	Estonia	Validated
Annual incidence	1-9 / 100 000	1.82	Finland	Validated
Annual incidence	1-9 / 100 000	2.54	France	Validated
Annual incidence	1-9 / 1 000 000	0.7	Germany	Validated
Annual incidence	1-9 / 1 000 000	0.74	Greece	Validated
Annual incidence	1-9 / 1 000 000	0.38	Hungary	Validated
Annual incidence	1-9 / 100 000	1.12	Ireland	Validated
Annual incidence	1-9 / 1 000 000	0.34	Latvia	Validated
Annual incidence	1-9 / 100 000	1.12	Lithuania	Validated
Annual incidence	1-9 / 100 000	2.6	Luxembourg	Validated
Annual incidence	1-9 / 1 000 000	0.34	Malta	Validated
Annual incidence	1-9 / 100 000	2.4	Netherlands	Validated
Annual incidence	<1 / 1 000 000	0.02	Poland	Validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0001945	Fever	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0025086	Bloody mucoid diarrhea	Very frequent (80-99%)
HP:0032155	Abdominal cramps	Very frequent (80-99%)
HP:0001944	Dehydration	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0003111	Abnormal blood ion concentration	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012702	Tenesmus	Frequent (30-79%)
HP:0025406	Asthenia	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Occasional (5-29%)
HP:0002590	Paralytic ileus	Occasional (5-29%)
HP:0002721	Immunodeficiency	Occasional (5-29%)
HP:0002902	Hyponatremia	Occasional (5-29%)
HP:0025085	Bloody diarrhea	Occasional (5-29%)
HP:0025615	Abscess	Occasional (5-29%)
HP:0031274	Hypovolemic shock	Occasional (5-29%)
HP:0100279	Ulcerative colitis	Occasional (5-29%)
HP:0100282	Acute colitis	Occasional (5-29%)
HP:0000509	Conjunctivitis	Very rare (<1-4%)
HP:0000554	Uveitis	Very rare (<1-4%)
HP:0000979	Purpura	Very rare (<1-4%)
HP:0001025	Urticaria	Very rare (<1-4%)
HP:0001369	Arthritis	Very rare (<1-4%)
HP:0001396	Cholestasis	Very rare (<1-4%)
HP:0001399	Hepatic failure	Very rare (<1-4%)
HP:0001873	Thrombocytopenia	Very rare (<1-4%)
HP:0001919	Acute kidney injury	Very rare (<1-4%)
HP:0001937	Microangiopathic hemolytic anemia	Very rare (<1-4%)
HP:0002090	Pneumonia	Very rare (<1-4%)
HP:0002586	Peritonitis	Very rare (<1-4%)
HP:0003201	Rhabdomyolysis	Very rare (<1-4%)
HP:0005575	Hemolytic-uremic syndrome	Very rare (<1-4%)
HP:0009830	Peripheral neuropathy	Very rare (<1-4%)
HP:0012804	Corneal ulceration	Very rare (<1-4%)
HP:0012819	Myocarditis	Very rare (<1-4%)
HP:0025059	Splenic abscess	Very rare (<1-4%)
HP:0031368	Intestinal perforation	Very rare (<1-4%)
HP:0031864	Bacteremia	Very rare (<1-4%)
HP:0100806	Sepsis	Very rare (<1-4%)
HP:0500006	Urethritis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	shigellosis
Mondo ID	MONDO:0019345
EFO	EFO:0005585
MeSH	D004405
Orphanet	810
DOID	DOID:12385
ICD-10-CM	A03
ICD-11	2080365623
NCIT	C157978
SNOMED CT	36188001
UMLS	C0013371
MedGen	8513
GARD	0004818
MedDRA	10017915, 10054178
Is cancer (heuristic)	no

Also known as: Shigella boydii infectious disease · Shigella flexneri infectious disease · Shigella sonnei infectious disease · shigellosis

Data availability: 12 GWAS associations (1 study).

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of primarily extrinsic mechanism › infectious disease › bacterial infectious disease › primary bacterial infectious disease › shigellosis

Related subtypes (36): Buruli ulcer disease, sennetsu fever, salmonellosis, pinta disease, chancroid, gonorrhea, anthrax infection, leprosy, botulism, diphtheria, tetanus, bartonellosis, brucellosis, campylobacteriosis, glanders, granuloma inguinale, legionellosis, leptospirosis, listeriosis, Mycobacterium avium complex disease, ornithosis, rhinoscleroma, staphyloenterotoxemia, syphilis, cholera, ehrlichiosis, melioidosis, tuberculosis, tularemia, plague, Q fever, Lyme disease, relapsing fever, spirillary rat-bite fever, streptobacillary rat-bite fever, Borrelia miyamotoi disease

Genetics & variants

GWAS landscape

12 GWAS associations across 1 studies. Top hits map to 8 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs582240	6e-08	KRT18P59 - PKNOX2-DT	?	0.43
rs12550437	1e-07	PPP1R3B-DT	?	0.48
rs10266841	1e-06	CYTH3	?	0.49
rs7920436	2e-06	MRPS21P5 - MPP7	?
rs35920088	3e-06	DRAM1	?
rs2518722	3e-06	MTAP - CDKN2A-AS1	?
rs147818229	3e-06	YME1L1	?
rs35260253	5e-06	EEF1A1P21 - RPS3AP17	?
chr5:58406871	6e-06		?
rs73352601	6e-06	MYLK4	?
rs62386195	7e-06	RIOK1	?
rs12041056	9e-06	C1orf141, IL23R	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST012207	Duchen D	2021	143	0	Host genome wide association study of infant susceptibility to Shigella-associated diarrhea.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	11

MAF distribution

Bucket	Variants
common (>=0.05)	10
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	2

Functional consequences

Consequence	Count
intron_variant	9
3_prime_UTR_variant	1
intergenic_variant	1
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs582240	11	125122939	C>A,G,T	0.05	intron_variant	KRT18P59 - PKNOX2-DT	6e-08	Tier 4: intronic/intergenic
rs12550437	8	9348021	G>A	0.05	intron_variant	PPP1R3B-DT	1e-07	Tier 4: intronic/intergenic
rs10266841	7	6164589	C>A,G,T	0.05	3_prime_UTR_variant	CYTH3	1e-06	Tier 2: splice/UTR
rs7920436	10	28047767	T>A,C,G	0.05	intron_variant	MRPS21P5 - MPP7	2e-06	Tier 4: intronic/intergenic
rs35920088	12	101915245	C>T	0.05	intron_variant	DRAM1	3e-06	Tier 4: intronic/intergenic
rs2518722	9	21952927	C>T	0.05	intron_variant	MTAP - CDKN2A-AS1	3e-06	Tier 4: intronic/intergenic
rs147818229	10	27148200			intron_variant	YME1L1	3e-06	Tier 4: intronic/intergenic
rs35260253	4	29829012	CAAAAAA>C,CAAA,CAAAA,CAAAAA,CAAAAAAA,CAAAAAAAA,CAAAAAAAAA,CAAAAAAAAAA,CAAAAAAAAAAA	0.05	intergenic_variant	EEF1A1P21 - RPS3AP17	5e-06	Tier 4: intronic/intergenic
chr5:58406871							6e-06	Tier 4: intronic/intergenic
rs73352601	6	2743777	A>G,T	0.05	intron_variant	MYLK4	6e-06	Tier 4: intronic/intergenic
rs62386195	6	7395251	C>A,T	0.05	intron_variant	RIOK1	7e-06	Tier 4: intronic/intergenic
rs12041056	1	67161577	C>T	0.05	intron_variant	C1orf141, IL23R	9e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
YME1L1	Orphanet:98676	Autosomal recessive isolated optic atrophy
PDE4D	Orphanet:439822	PDE4D haploinsufficiency syndrome
PDE4D	Orphanet:950	Acrodysostosis

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
YME1L1	HGNC:12843	ENSG00000136758	Q96TA2	ATP-dependent zinc metalloprotease YME1L1	gwas
RIOK1	HGNC:18656	ENSG00000124784	Q9BRS2	Serine/threonine-protein kinase RIO1	gwas
DRAM1	HGNC:25645	ENSG00000136048	Q8N682	DNA damage-regulated autophagy modulator protein 1	gwas
MYLK4	HGNC:27972	ENSG00000145949	Q86YV6	Myosin light chain kinase family member 4	gwas
C1orf141	HGNC:32044	ENSG00000203963	Q5JVX7	Uncharacterized protein C1orf141	gwas
KRT18P59	HGNC:48886	ENSG00000187686		keratin 18 pseudogene 59	gwas
PDE4D	HGNC:8783	ENSG00000113448	Q08499	3’,5’-cyclic-AMP phosphodiesterase 4D	gwas
CYTH3	HGNC:9504	ENSG00000008256	O43739	Cytohesin-3	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
YME1L1	ATP-dependent zinc metalloprotease YME1L1	ATP-dependent metalloprotease that catalyzes the degradation of folded and unfolded proteins with a suitable degron sequence in the mitochondrial intermembrane region.
RIOK1	Serine/threonine-protein kinase RIO1	Involved in the final steps of cytoplasmic maturation of the 40S ribosomal subunit.
DRAM1	DNA damage-regulated autophagy modulator protein 1	Lysosomal modulator of autophagy that plays a central role in p53/TP53-mediated apoptosis.
PDE4D	3’,5’-cyclic-AMP phosphodiesterase 4D	Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
CYTH3	Cytohesin-3	Promotes guanine-nucleotide exchange on ARF1 and ARF6.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.5

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
Kinase	2	6.9×	0.157
Protease	1	4.6×	0.497
Scaffold/PPI	1	2.2×	0.627
Enzyme (other)	1	1.5×	0.627
Other/Unknown	3	0.7×	0.919

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
YME1L1	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
RIOK1	Kinase	yes		RIO_kinase, Kinase-like_dom_sf, Ser/Thr_kinase_Rio1
DRAM1	Other/Unknown	no		CWH43_N, DRAM/TMEM150_Autophagy_Mod
MYLK4	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
C1orf141	Other/Unknown	no		DUF4545
KRT18P59	Other/Unknown	no
PDE4D	Enzyme (other)	yes	3.1.4.53	PDEase_catalytic_dom, PDEase, PDEase_CS
CYTH3	Scaffold/PPI	no		Sec7_dom, PH_domain, PH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

7 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
parietal pleura	2
biceps brachii	2
male germ line stem cell (sensu Vertebrata) in testis	2
testis	2
germinal epithelium of ovary	1
tibia	1
epithelial cell of pancreas	1
primordial germ cell in gonad	1
secondary oocyte	1
lower lobe of lung	1
upper lobe of left lung	1
upper lobe of lung	1
deltoid	1
skeletal muscle tissue of biceps brachii	1
right uterine tube	1
left testis	1
gluteal muscle	1
skeletal muscle tissue of rectus abdominis	1
endothelial cell	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
YME1L1	295	ubiquitous	marker	germinal epithelium of ovary, tibia, parietal pleura
RIOK1	237	ubiquitous	marker	epithelial cell of pancreas, primordial germ cell in gonad, secondary oocyte
DRAM1	235	ubiquitous	marker	lower lobe of lung, upper lobe of lung, upper lobe of left lung
MYLK4	172	tissue_specific	yes	biceps brachii, deltoid, skeletal muscle tissue of biceps brachii
C1orf141	63	tissue_specific	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, testis
KRT18P59	36		marker	male germ line stem cell (sensu Vertebrata) in testis, testis, left testis
PDE4D	283	ubiquitous	marker	gluteal muscle, biceps brachii, skeletal muscle tissue of rectus abdominis
CYTH3	266	ubiquitous	marker	endothelial cell, visceral pleura, parietal pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
YME1L1	4,274
RIOK1	2,935
MYLK4	1,646
PDE4D	1,533
DRAM1	843
CYTH3	819
C1orf141	594
KRT18P59	0

Structural data

PDB: 4 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE4D	Q08499	122
RIOK1	Q9BRS2	10
CYTH3	O43739	3
MYLK4	Q86YV6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DRAM1	Q8N682	94.73
YME1L1	Q96TA2	70.79
C1orf141	Q5JVX7	47.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 8 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cellular response to mitochondrial stress	1	285.5×	0.022	YME1L1
Processing of SMDT1	1	158.6×	0.022	YME1L1
DARPP-32 events	1	119.0×	0.022	PDE4D
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	89.2×	0.022	PDE4D
Intra-Golgi traffic	1	64.9×	0.025	CYTH3
Mitochondrial protein degradation	1	28.6×	0.046	YME1L1
G alpha (s) signalling events	1	18.3×	0.061	PDE4D
Major pathway of rRNA processing in the nucleolus and cytosol	1	15.4×	0.063	RIOK1

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
negative regulation of relaxation of cardiac muscle	1	1404.3×	0.011	PDE4D
negative regulation of heart contraction	1	702.2×	0.011	PDE4D
cellular response to oxygen-glucose deprivation	1	702.2×	0.011	DRAM1
positive regulation of mitochondrial fusion	1	561.7×	0.011	YME1L1
mitochondrial protein processing	1	468.1×	0.011	YME1L1
cAMP catabolic process	1	312.1×	0.011	PDE4D
adrenergic receptor signaling pathway	1	312.1×	0.011	PDE4D
regulation of cell communication by electrical coupling involved in cardiac conduction	1	312.1×	0.011	PDE4D
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	280.9×	0.011	PDE4D
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	280.9×	0.011	PDE4D
positive regulation of rRNA processing	1	280.9×	0.011	RIOK1
mitochondrial protein catabolic process	1	255.3×	0.011	YME1L1
Golgi vesicle transport	1	255.3×	0.011	CYTH3
positive regulation of interleukin-5 production	1	234.1×	0.011	PDE4D
protein hexamerization	1	234.1×	0.011	YME1L1
regulation of stem cell division	1	234.1×	0.011	YME1L1
cellular response to epinephrine stimulus	1	216.1×	0.011	PDE4D
establishment of epithelial cell polarity	1	200.6×	0.012	CYTH3
regulation of cardiac muscle cell contraction	1	187.2×	0.012	PDE4D
regulation of ARF protein signal transduction	1	147.8×	0.014	CYTH3
protein quality control for misfolded or incompletely synthesized proteins	1	127.7×	0.014	YME1L1
maturation of SSU-rRNA	1	127.7×	0.014	RIOK1
establishment of endothelial barrier	1	127.7×	0.014	PDE4D
positive regulation of heart rate	1	117.0×	0.014	PDE4D
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	112.3×	0.014	PDE4D
neuronal stem cell population maintenance	1	112.3×	0.014	YME1L1
negative regulation of cAMP/PKA signal transduction	1	100.3×	0.015	PDE4D
regulation of heart rate	1	78.0×	0.018	PDE4D
positive regulation of interleukin-2 production	1	78.0×	0.018	PDE4D
cellular response to cAMP	1	48.4×	0.029	PDE4D

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Azithromycin, Ceftriaxone, Sodium Chloride, Tebipenem Pivoxil.

Drug target analysis

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

Druggability breadth: 4 of 8 evidence-associated genes (50%) 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
RIOK1	FEDRATINIB
MYLK4	FEDRATINIB
PDE4D	INAMRINONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE4D	269	4
RIOK1	19	4
MYLK4	13	4
YME1L1	0	0
DRAM1	0	0
C1orf141	0	0
KRT18P59	0	0
CYTH3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	MYLK4, PDE4D, RIOK1
AXITINIB	4	RIOK1
RUXOLITINIB	4	RIOK1
BOSUTINIB	4	RIOK1
NINTEDANIB	4	MYLK4, RIOK1
SUNITINIB	4	MYLK4, PDE4D, RIOK1
CRIZOTINIB	4	PDE4D, RIOK1
MIDOSTAURIN	4	MYLK4, RIOK1
INAMRINONE	4	PDE4D
THEOPHYLLINE	4	PDE4D
VARDENAFIL	4	PDE4D
MILRINONE	4	PDE4D
LOSARTAN	4	PDE4D
SILDENAFIL	4	PDE4D
ROFLUMILAST	4	PDE4D
ENOXIMONE	4	PDE4D
ENSIFENTRINE	4	PDE4D
CRISABOROLE	4	PDE4D
APREMILAST	4	PDE4D
PENTOXIFYLLINE	4	PDE4D
TADALAFIL	4	PDE4D
DIPYRIDAMOLE	4	PDE4D
CANDESARTAN CILEXETIL	4	PDE4D
TELMISARTAN	4	PDE4D
SIMVASTATIN	4	PDE4D
MORICIZINE	4	PDE4D
AMLEXANOX	4	PDE4D
AMOXAPINE	4	PDE4D
PONATINIB	4	PDE4D
RUCAPARIB	4	PDE4D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PDE4D	863	Binding:805, Functional:33, ADMET:23, Toxicity:2
MYLK4	113	Binding:113
RIOK1	104	Binding:104
CYTH3	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
YME1L1	3.4.24.B18
PDE4D	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RIOK1	104
MYLK4	113
PDE4D	863

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

30 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)
FEDRATINIB	4	MYLK4, PDE4D, RIOK1
AXITINIB	4	RIOK1
RUXOLITINIB	4	RIOK1
BOSUTINIB	4	RIOK1
NINTEDANIB	4	MYLK4, RIOK1
SUNITINIB	4	MYLK4, PDE4D, RIOK1
CRIZOTINIB	4	PDE4D, RIOK1
MIDOSTAURIN	4	MYLK4, RIOK1
INAMRINONE	4	PDE4D
THEOPHYLLINE	4	PDE4D
VARDENAFIL	4	PDE4D
MILRINONE	4	PDE4D
LOSARTAN	4	PDE4D
SILDENAFIL	4	PDE4D
ROFLUMILAST	4	PDE4D
ENOXIMONE	4	PDE4D
ENSIFENTRINE	4	PDE4D
CRISABOROLE	4	PDE4D
APREMILAST	4	PDE4D
PENTOXIFYLLINE	4	PDE4D
TADALAFIL	4	PDE4D
DIPYRIDAMOLE	4	PDE4D
CANDESARTAN CILEXETIL	4	PDE4D
TELMISARTAN	4	PDE4D
SIMVASTATIN	4	PDE4D
MORICIZINE	4	PDE4D
AMLEXANOX	4	PDE4D
AMOXAPINE	4	PDE4D
PONATINIB	4	PDE4D
RUCAPARIB	4	PDE4D

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	RIOK1, MYLK4, PDE4D
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	YME1L1
E	Difficult family or no structure, no drug	4	DRAM1, C1orf141, KRT18P59, CYTH3

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)
YME1L1	0	—
DRAM1	0	—
C1orf141	0	—
KRT18P59	0	—
CYTH3	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 24.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	12
PHASE2	5
PHASE1/PHASE2	3
PHASE3	2
PHASE4	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03854929	PHASE4	COMPLETED	Ciprofloxacin Versus Azithromycin for Children Hospitalised With Dysentery
NCT00368316	PHASE3	COMPLETED	Safety, Immunogenicity and Efficacy of Shigella Conjugate Vaccines in 1-4 Year Olds in Israel
NCT05156528	PHASE3	UNKNOWN	Efficacy, Immunogenicity and Safety of S. Flexneriza-S. Sonnei Bivalent Conjugate Vaccine in Volunteers Aged From 6 Months to 5 Years
NCT05121974	PHASE2	ACTIVE_NOT_RECRUITING	Tebipenem Trial in Children With Shigellosis
NCT05182749	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of the Bacteriophage Preparation, ShigActive™, in a Human Experimental Model of Shigellosis
NCT06615375	PHASE2	ACTIVE_NOT_RECRUITING	A Human Challenge Study to Assess Protection of a Shigella Tetravalent Bioconjugate Vaccine
NCT00485134	PHASE1/PHASE2	COMPLETED	Shigella Flexneri 2a Invaplex 50 Vaccine Dose Finding and Assessment of Protection
NCT00800930	PHASE2	COMPLETED	Therapeutic Induction of Endogenous Antibiotics
NCT02646371	PHASE2	COMPLETED	Phase 2b Challenge Study With the Bioconjugate Vaccine Flexyn2a
NCT04056117	PHASE1/PHASE2	COMPLETED	A Study to Determine If a New Shigella Vaccine is Safe, Induces Immunity and The Best Dose Among Kenyan Infants
NCT06523231	PHASE2	COMPLETED	Study to Expand Safety and Immunogenicity Data With Shigella Bioconjugate Vaccine (Shigella4V2) in 9-month-old Infants.
NCT05959616	PHASE1	RECRUITING	Shigella Sonnei 53G Human Infection Study in Kenyan Adults
NCT05961059	PHASE1	RECRUITING	InvaplexAR-Detox and DmLT Adjuvant in the Netherlands and Zambia
NCT01069471	PHASE1	COMPLETED	Safety and Reactogenicity of Bioconjugate Vaccine to Prevent Shigella
NCT01369927	PHASE1	COMPLETED	Shigella Sonnel O-SPC/rBRU Conjugate Vaccine
NCT01399424	PHASE1	WITHDRAWN	Shigella Sonnei OSPC-rDT Conjugate Vaccine
NCT01509846	PHASE1	COMPLETED	Safety Study of Inactivated Shigella Whole Cell Vaccine in Adults
NCT02017899	PHASE1	COMPLETED	A Phase 1, Dose Escalation Study, to Evaluate a New Shigella Sonnei Vaccine in Healthy Adults.
NCT02034500	PHASE1	COMPLETED	Evaluate a New Shigella Sonnei Vaccine Administered Either by Intradermal, Intranasal or Intramuscular Route in Healthy Adults
NCT02388009	PHASE1	COMPLETED	Safety and Tolerability of a Bioconjugate Vaccine Against Shigella Flexneri 2a
NCT02445963	PHASE1	COMPLETED	Safety and Immunogenicity of Artificial Invaplex (Shigella Flexneri 2a InvaplexAR)
NCT02797236	PHASE1	COMPLETED	SF2a-TT15 Conjugate Vaccine in Healthy Adult Volunteers
NCT04992520	PHASE1	COMPLETED	Controlled Human Infection Model Challenge/Rechallenge
NCT02105714	Not specified	COMPLETED	Diagnosis of Neglected Tropical Diseases Among Patients With Persistent Digestive Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AZITHROMYCIN	4	1
CEFTRIAXONE	4	1
CIPROFLOXACIN	4	1
TEBIPENEM PIVOXIL	3	1
SODIUM BUTYRATE	2	1
CHEMBL4299381	0	2