SARM1

Summary

SARM1 (sterile alpha and TIR motif containing 1, HGNC:17074) is a protein-coding gene on chromosome 17q11.2, encoding NAD(+) hydrolase SARM1 (Q6SZW1). NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism.

Enables NAD+ nucleosidase activity; NAD+ nucleosidase activity, cyclic ADP-ribose generating; and identical protein binding activity. Involved in NAD catabolic process and response to axon injury. Is active in mitochondrion.

Source: NCBI Gene 23098 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 172 total — 3 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015077

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17074
Approved symbol	SARM1
Name	sterile alpha and TIR motif containing 1
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	SARM, SAMD2, KIAA0524
Ensembl gene	ENSG00000004139
Ensembl biotype	protein_coding
OMIM	607732
Entrez	23098

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000379061, ENST00000577870, ENST00000578128, ENST00000579593, ENST00000580711, ENST00000582323, ENST00000585453, ENST00000585482, ENST00000886313, ENST00000944181

RefSeq mRNA: 1 — MANE Select: NM_015077 NM_015077

CCDS: CCDS11230

Canonical transcript exons

ENST00000585482 — 9 exons

Exon	Start	End
ENSE00002702881	28396157	28404049
ENSE00003502782	28388350	28388539
ENSE00003570258	28381203	28381821
ENSE00003619537	28385040	28385275
ENSE00003721884	28395905	28396026
ENSE00003724822	28371694	28372502
ENSE00003725931	28388174	28388276
ENSE00003746027	28384839	28384930
ENSE00003752635	28384357	28384569

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 88.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.5624 / max 282.2217, expressed in 1587 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160014	8.6674	1273
160015	3.9432	1085
160020	1.8131	827
160021	1.6157	502
160013	0.5043	202
160016	0.3480	199
160019	0.2570	128
160018	0.1428	67
160022	0.1311	77
160017	0.0814	33

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	88.67	gold quality
cortical plate	UBERON:0005343	88.09	gold quality
islet of Langerhans	UBERON:0000006	87.62	gold quality
pancreas	UBERON:0001264	87.25	gold quality
ganglionic eminence	UBERON:0004023	87.18	gold quality
ventricular zone	UBERON:0003053	85.69	gold quality
adenohypophysis	UBERON:0002196	84.84	gold quality
pituitary gland	UBERON:0000007	84.66	gold quality
granulocyte	CL:0000094	84.57	gold quality
right uterine tube	UBERON:0001302	84.46	gold quality
stromal cell of endometrium	CL:0002255	83.62	gold quality
right adrenal gland	UBERON:0001233	83.38	gold quality
body of uterus	UBERON:0009853	83.21	gold quality
spleen	UBERON:0002106	82.97	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.88	gold quality
right frontal lobe	UBERON:0002810	82.83	gold quality
right adrenal gland cortex	UBERON:0035827	82.79	gold quality
left adrenal gland	UBERON:0001234	82.24	gold quality
popliteal artery	UBERON:0002250	82.12	gold quality
tibial artery	UBERON:0007610	82.10	gold quality
cerebellar hemisphere	UBERON:0002245	82.07	gold quality
cerebellar cortex	UBERON:0002129	82.05	gold quality
prefrontal cortex	UBERON:0000451	82.00	gold quality
left adrenal gland cortex	UBERON:0035825	81.79	gold quality
body of stomach	UBERON:0001161	81.62	gold quality
nucleus accumbens	UBERON:0001882	81.62	gold quality
aorta	UBERON:0000947	81.56	gold quality
adrenal cortex	UBERON:0001235	81.46	gold quality
cerebellum	UBERON:0002037	81.06	gold quality
metanephros cortex	UBERON:0010533	80.97	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	2407.15
E-ANND-3	yes	2.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

270 targeting SARM1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-2110	99.96	66.68	1930

Literature-anchored findings (GeneRIF, showing 40)

• Candidate gene in the onset of hereditary infectious/inflammatory diseases. (PMID:15893701)
• TIR adaptor SARM is a negative regulator of Toll-like receptor signaling. (PMID:16964262)
• confirmed the co-localization of retinoschisin with Na/K ATPase and SARM1 in photoreceptors and bipolar cells of retina tissue (PMID:17804407)
• SARM1 deficiencies may uncover unexpected similarities between the ways in which neurons and immune cells sense and respond to danger. (PMID:18089857)
• SARM-mediated inhibition may not be exclusively directed at TRIF or MyD88, but that SARM may also directly inhibit MAPK phosphorylation (PMID:20306472)
• The N-terminal 27 amino acids (S27) of SARM, which is hydrophobic and polybasic, acts as a mitochondria-targeting signal sequence, associating SARM to the mitochondria. The S27 peptide has an inherent ability to bind to lipids and mitochondria. (PMID:22145856)
• SARM overexpression caused mitochondrial clustering which has also been observed in several cell death phenomenon. (PMID:23175186)
• These results indicate that association of PINK1 with SARM1 and TRAF6 is an important step for mitophagy. (PMID:23885119)
• The innate immunity adaptor SARM translocates to the nucleus to stabilize lamins and prevent DNA fragmentation in response to pro-apoptotic signaling. (PMID:23923041)
• Data found that the UXT isoforms elicit dual opposing regulatory effects on SARM-induced apoptosis. (PMID:24021647)
• Rapid Wallerian degeneration requires the pro-degenerative molecules SARM1. (PMID:24840802)
• Data show that sterile alpha- and armadillo-motif-containing protein (SARM) modulates MyD88 protein-mediated Toll-like receptors (TLRs) activation through BB-loop dependent interleukin-1 receptor (TIR) TIR-TIR interactions. (PMID:26592460)
• Active nerve degeneration requires SARM1 and MAP kinases, including DLK, while the NAD+ synthetic enzyme NMNAT2 prevents degeneration. (PMID:26844829)
• we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury. (PMID:27671644)
• SARM1 is phosphorylated at Ser-548 by c-jun-N-terminal kinase under conditions of oxidative stress, and this increases SARM1’s NADase activity, leading to inhibited mitochondrial respiration and decreased levels of NAD+ and ATP. (PMID:30333228)
• These results highlight the importance of oligomerization for SARM1 function and reveal critical epitopes for future targeted drug development. (PMID:31278906)
• Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program. (PMID:31484833)
• The SARM1 axon degeneration pathway: control of the NAD(+) metabolome regulates axon survival in health and disease. (PMID:32311648)
• lncRNA OGFRP1 functions as a ceRNA to promote the progression of prostate cancer by regulating SARM1 level via miR-124-3p. (PMID:32428870)
• The NAD(+)-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. (PMID:33053563)
• Structural basis for SARM1 inhibition and activation under energetic stress. (PMID:33185189)
• Multiple domain interfaces mediate SARM1 autoinhibition. (PMID:33468661)
• SARM1 is required in human derived sensory neurons for injury-induced and neurotoxic axon degeneration. (PMID:33548217)
• Expression of sterile-alpha and armadillo motif containing protein (SARM) in rheumatoid arthritis monocytes correlates with TLR2-induced IL-1beta and disease activity. (PMID:33605409)
• Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon. (PMID:33871822)
• Acidic pH irreversibly activates the signaling enzyme SARM1. (PMID:34213829)
• SARM1-mediated wallerian degeneration: A possible mechanism underlying organophosphorus-induced delayed neuropathy. (PMID:34455132)
• The curious case of SARM1: Dr. Jekyll and Mr. Hyde in cell death and immunity? (PMID:34710262)
• Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders. (PMID:34796871)
• Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN. (PMID:34935867)
• Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients. (PMID:34991663)
• Circ_0044516 Enriches the Level of SARM1 as a miR-330-5p Sponge to Regulate Cell Malignant Behaviors and Tumorigenesis of Prostate Cancer. (PMID:34993722)
• SARM1 can be a potential therapeutic target for spinal cord injury. (PMID:35224705)
• TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line. (PMID:35468924)
• Natural variants of human SARM1 cause both intrinsic and dominant loss-of-function influencing axon survival. (PMID:35974060)
• TIR-1/SARM1 inhibits axon regeneration and promotes axon degeneration. (PMID:37083456)
• A phase transition reduces the threshold for nicotinamide mononucleotide-based activation of SARM1, an NAD(P) hydrolase, to physiologically relevant levels. (PMID:37742918)
• The SARM1 TIR domain produces glycocyclic ADPR molecules as minor products. (PMID:38635746)
• Context-Specific Stress Causes Compartmentalized SARM1 Activation and Local Degeneration in Cortical Neurons. (PMID:38692735)
• Augustus Waller’s foresight realized: SARM1 in peripheral neuropathies. (PMID:38852438)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sarm1	ENSDARG00000010610
mus_musculus	Sarm1	ENSMUSG00000050132
rattus_norvegicus	Sarm1	ENSRNOG00000010244
drosophila_melanogaster	Sarm	FBGN0262579
caenorhabditis_elegans		WBGENE00006575

Protein

Protein identifiers

NAD(+) hydrolase SARM1 — Q6SZW1 (reviewed: Q6SZW1)

Alternative names: NADP(+) hydrolase SARM1, Sterile alpha and Armadillo repeat protein, Sterile alpha and TIR motif-containing protein 1, Sterile alpha motif domain-containing protein 2, Tir-1 homolog

All UniProt accessions (4): Q6SZW1, J3KRZ6, J3KSG7, J3QRE0

UniProt curated annotations — full annotation on UniProt →

Function. NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism. Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site. Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, SARM1 is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting cytoskeletal degradation and axon destruction. Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules. Can activate neuronal cell death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response: inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.

Subunit / interactions. Homooctamer; forms an octameric ring via SAM domains. Interacts with TICAM1/TRIF and thereby interferes with TICAM1/TRIF function. Interacts with MAPK10/JNK3 and SDC2 (via cytoplasmic domain).

Subcellular location. Cytoplasm. Cell projection. Axon. Dendrite. Synapse. Mitochondrion.

Tissue specificity. Predominantly expressed in brain, kidney and liver. Expressed at lower level in placenta.

Post-translational modifications. Phosphorylation at Ser-548 by JNK kinases (MAPK8, MAPK9 and /or MAPK10) enhance the NAD(+) hydrolase (NADase) activity. Phosphorylation at Ser-548 and subsequent activation takes place in response to oxidative stress conditions and inhibits mitochondrial respiration.

Activity regulation. Autoinhibited: in the inactive state, the enzymatic TIR domain is held apart by the autoinhibiting ARM repeats. NAD(+)-binding to ARM repeats maintains an inactive state by promoting interaction between ARM repeats and the TIR domain, thereby facilitating inhibition of the enzymatic TIR domain. Following activation, possibly by nicotinamide mononucleotide (NMN), auto-inhibitory interactions are released, allowing self-association of the TIR domains and subsequent activation of the NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is facilitated by the octamer of SAM domains. NAD(+) hydrolase activity is inhibited by nicotinamide. Specifically inhibited by berberine chloride and zinc chloride.

Domain organisation. The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. The ARM repeats inhibit the NAD(+) hydrolase (NADase) activity by binding to NAD(+): NAD(+)-binding to ARM repeats facilitates inhibition of the TIR domain NADase through their domain interface. In contrast to classical ARM repeats, the last helix of ARM 6 does not fold back to interact with the first two helices, but instead turns towards the N-terminus of SARM1. As a result, the two following motifs ARM 7 and ARM 8 reverse their directions and lie perpendicularly. Moreover, ARM repeats interact with different domains not only within each protomer but also of the adjacent ones.

Induction. Up-regulated by lipopolysaccharides (LPS).

Similarity. Belongs to the SARM1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6SZW1-1	1	yes
Q6SZW1-2	2

RefSeq proteins (1): NP_055892* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR001660	SAM	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily
IPR039184	SARM1	Family

Pfam: PF07647, PF13676

Catalyzed reactions (Rhea), 3 shown:

• NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (RHEA:16301)
• NADP(+) + H2O = ADP-D-ribose 2’-phosphate + nicotinamide + H(+) (RHEA:19849)
• NAD(+) = cyclic ADP-beta-D-ribose + nicotinamide + H(+) (RHEA:38611)

UniProt features (152 total): mutagenesis site 62, helix 44, turn 11, strand 10, repeat 8, binding site 6, domain 3, modified residue 2, transit peptide 1, chain 1, region of interest 1, active site 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

55 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7NAJ	X-RAY DIFFRACTION	1.6
6O1B	X-RAY DIFFRACTION	1.67
7NAG	X-RAY DIFFRACTION	1.72
9HQF	X-RAY DIFFRACTION	1.73
7NAI	X-RAY DIFFRACTION	1.74
8D0F	X-RAY DIFFRACTION	1.74
9MW2	X-RAY DIFFRACTION	1.75
10RA	X-RAY DIFFRACTION	1.79
7NAH	X-RAY DIFFRACTION	1.79
6O0Q	X-RAY DIFFRACTION	1.8
6O0R	X-RAY DIFFRACTION	1.8
8D0E	X-RAY DIFFRACTION	1.88
10RC	X-RAY DIFFRACTION	1.9
9MW3	X-RAY DIFFRACTION	1.93
8D0J	X-RAY DIFFRACTION	1.94
8D0D	X-RAY DIFFRACTION	1.96
9HQH	X-RAY DIFFRACTION	1.99
8D0G	X-RAY DIFFRACTION	1.99
8D0I	X-RAY DIFFRACTION	2
10RB	X-RAY DIFFRACTION	2.05
6O0V	X-RAY DIFFRACTION	2.07
8D0C	X-RAY DIFFRACTION	2.09
9MW1	X-RAY DIFFRACTION	2.1
9HQ0	X-RAY DIFFRACTION	2.13
8D0H	X-RAY DIFFRACTION	2.37
9L2E	ELECTRON MICROSCOPY	2.46
6QWV	X-RAY DIFFRACTION	2.47
7CM5	ELECTRON MICROSCOPY	2.6
7CM7	ELECTRON MICROSCOPY	2.6
7ANW	ELECTRON MICROSCOPY	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6SZW1-F1	86.48	0.74

Antibody-complex structures (SAbDab): 3 — 8GNI, 8GNJ, 8GQ5

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 642

Ligand- & substrate-binding residues (6): 103; 110; 149–157; 190–193; 569–570; 599

Post-translational modifications (2): 548, 558

Mutagenesis-validated functional residues (62):

Position	Phenotype
11	no effect on mitochondrial localization.
14	loss in ability to localize to mitochondria and reduction in apoptotic activity.
22	no effect on mitochondrial localization.
27	no effect on mitochondrial localization.
103	in wqh to a mutant: increased nad(+)-binding to arm repeats, leading to decreased nad(+) hydrolase activity; when associ
110	in rrk to a mutant: slightly reduced nad(+)-binding to arm repeats; when associated with a-157 and a-193.
110	in rrk to e mutant: strongly reduced nad(+)-binding to arm repeats, leading to enhanced nad(+) hydrolase activity and co
150	in wqh to a mutant: increased nad(+)-binding to arm repeats, leading to decreased nad(+) hydrolase activity; when associ
157	in rrk to a mutant: slightly reduced nad(+)-binding to arm repeats; when associated with a-110 and a-193.
157	in rrk to e mutant: strongly reduced nad(+)-binding to arm repeats, leading to enhanced nad(+) hydrolase activity and co
190	in wqh to a mutant: increased nad(+)-binding to arm repeats, leading to decreased nad(+) hydrolase activity; when associ
193	in rrk to a mutant: slightly reduced nad(+)-binding to arm repeats; when associated with a-110 and a-157.
193	in rrk to e mutant: strongly reduced nad(+)-binding to arm repeats, leading to enhanced nad(+) hydrolase activity and co
249	no effect on octamer formation; does not affect nad(+) hydrolase activity.
253	constitutively active mutant; strong ability to trigger axonal degeneration caused by disrupted interaction between the
259	no effect on octamer formation. shows increased nad(+) hydrolase activity and ability to trigger axonal degeneration.
261	no effect on octamer formation; does not affect nad(+) hydrolase activity.
408	does not affect phosphorylation level.
411	does not affect phosphorylation level.
419	does not affect phosphorylation level.
427	does not affect phosphorylation level.
432	does not affect phosphorylation level.
447	does not affect phosphorylation level.
453	does not affect phosphorylation level.
454	reduced ability to form an octameric ring and promote axonal degeneration following injury.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-936964	Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)
R-HSA-937041	IKK complex recruitment mediated by RIP1
R-HSA-937072	TRAF6-mediated induction of TAK1 complex within TLR4 complex

MSigDB gene sets: 206 (showing top): REACTOME_TRAF6_MEDIATED_INDUCTION_OF_TAK1_COMPLEX_WITHIN_TLR4_COMPLEX, REACTOME_IKK_COMPLEX_RECRUITMENT_MEDIATED_BY_RIP1, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, REACTOME_INNATE_IMMUNE_SYSTEM, HNF3ALPHA_Q6, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_RESPONSE_TO_AXON_INJURY, chr17q11, MODULE_503, GOBP_NADPLUS_METABOLIC_PROCESS

GO Biological Process (15): signal transduction (GO:0007165), nervous system development (GO:0007399), response to glucose (GO:0009749), NAD+ catabolic process (GO:0019677), cell differentiation (GO:0030154), negative regulation of MyD88-independent toll-like receptor signaling pathway (GO:0034128), regulation of neuron apoptotic process (GO:0043523), innate immune response (GO:0045087), response to axon injury (GO:0048678), regulation of dendrite morphogenesis (GO:0048814), nervous system process (GO:0050877), protein localization to mitochondrion (GO:0070585), modification of postsynaptic structure (GO:0099010), regulation of synapse pruning (GO:1905806), immune system process (GO:0002376)

GO Molecular Function (7): NAD+ nucleosidase activity (GO:0003953), signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), NADP+ nucleosidase activity (GO:0050135), NAD+ nucleosidase activity, cyclic ADP-ribose generating (GO:0061809), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (15): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), microtubule (GO:0005874), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), neuromuscular junction (GO:0031594), protein-containing complex (GO:0032991), synapse (GO:0045202), glutamatergic synapse (GO:0098978), extrinsic component of synaptic membrane (GO:0099243), microtubule cytoskeleton (GO:0015630), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TRIF (TICAM1)-mediated TLR4 signaling	3
Toll Like Receptor 4 (TLR4) Cascade	1
Toll-like Receptor Cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
hydrolase activity, hydrolyzing N-glycosyl compounds	3
cytoplasm	2
neuron projection	2
synapse	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
response to hexose	1
purine nucleotide catabolic process	1
pyridine nucleotide catabolic process	1
NAD+ metabolic process	1
cellular developmental process	1
MyD88-independent toll-like receptor signaling pathway	1
negative regulation of toll-like receptor signaling pathway	1
regulation of MyD88-independent toll-like receptor signaling pathway	1
regulation of apoptotic process	1
neuron apoptotic process	1
immune response	1
defense response to symbiont	1
response to wounding	1
regulation of anatomical structure morphogenesis	1
dendrite morphogenesis	1
regulation of dendrite development	1
system process	1
protein localization to organelle	1
modification of synaptic structure	1
regulation of synapse organization	1
synapse pruning	1
biological_process	1
protein-macromolecule adaptor activity	1
protein binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1

Protein interactions and networks

STRING

880 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SARM1	TLR4	O00206	952
SARM1	MYD88	P78397	936
SARM1	TICAM1	Q8IUC6	914
SARM1	TIRAP	P58753	895
SARM1	TLR3	O15455	886
SARM1	NMNAT2	Q9BZQ4	848
SARM1	TRAF6	Q9Y4K3	828
SARM1	IRF3	Q14653	820
SARM1	NMNAT1	Q9HAN9	795
SARM1	A0A2R8YFG2	A0A2R8YFG2	709
SARM1	RS1	O15537	691
SARM1	AR	P10275	682
SARM1	TLR7	Q9NYK1	668
SARM1	SAMD4A	Q9UPU9	663
SARM1	IRF7	Q92985	660

IntAct

51 interactions, top by confidence:

A	B	Type	Score
CARNMT1	NUP42	psi-mi:“MI:0914”(association)	0.640
SARM1	MYD88	psi-mi:“MI:0407”(direct interaction)	0.620
SARM1	MYD88	psi-mi:“MI:0403”(colocalization)	0.620
MYD88	SARM1	psi-mi:“MI:0915”(physical association)	0.620
SARM1	TICAM2	psi-mi:“MI:0407”(direct interaction)	0.590
TICAM2	SARM1	psi-mi:“MI:0915”(physical association)	0.590
GHITM	CCNB2	psi-mi:“MI:0914”(association)	0.530
ZG16B	ITIH2	psi-mi:“MI:0914”(association)	0.530
RHOT2	UBC	psi-mi:“MI:0914”(association)	0.530
SARM1	TICAM1	psi-mi:“MI:0407”(direct interaction)	0.440
SARM1	TIRAP	psi-mi:“MI:0407”(direct interaction)	0.440
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
RS1	ATP1A3	psi-mi:“MI:0914”(association)	0.350
CAV3	SHTN1	psi-mi:“MI:0914”(association)	0.350
C1orf87	SNX2	psi-mi:“MI:0914”(association)	0.350
POC1B	TACC1	psi-mi:“MI:0914”(association)	0.350
CHRM4	GEMIN2	psi-mi:“MI:0914”(association)	0.350
RHOT2	BTAF1	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
rep	GPR89A	psi-mi:“MI:0914”(association)	0.350
rep	PSMD9	psi-mi:“MI:0914”(association)	0.350
rep	B4GALT3	psi-mi:“MI:0914”(association)	0.350
SHANK3	IGKV3D-15	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
RIMS1	PSMD12	psi-mi:“MI:0914”(association)	0.350
CARNMT1	LENG9	psi-mi:“MI:0914”(association)	0.350

BioGRID (82): SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-Western), SARM1 (Affinity Capture-MS), SARM1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A1A4Q9, A5YM72, A6NLP5, D3KCC4, I3L5V6, O43292, P10938, Q00973, Q05B52, Q09200, Q10468, Q14623, Q148G5, Q16586, Q2V8X7, Q3SZV0, Q561R2, Q5E9M9, Q5M868, Q5ZL13, Q66H45, Q69ZF3, Q6P3D0, Q6P7A1, Q6P9Z4, Q6SZW1, Q6TEC1, Q6ZPS2, Q7TMC8, Q864R5, Q86TX2, Q8IXI1, Q8N0W3, Q8N3Y3, Q8N6R0, Q8NF37, Q8NI29, Q8TCD5, Q8VBW8

Diamond homologs: A0AUS0, A1CJY4, A1D7I5, A2ZLU6, B0XAF3, B0XYC8, B8M0Q1, C6L7U1, D1FP53, D1FP57, D3ZUM2, E4NKF8, G1SJB4, G4MQX3, I3L5V6, O22193, O23225, O42248, O48700, O48847, O74653, O80742, O81902, P0C6E7, P38129, P63243, P63244, P63245, P63246, P63247, P68040, Q058P4, Q09715, Q0DR28, Q0IMG9, Q0WUF6, Q10FT0, Q10PI9, Q3E9F5, Q3E9F7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SARM1	down-regulates	TICAM1	binding
MAPK8	“down-regulates activity”	SARM1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

172 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	89
Likely benign	39
Benign	26

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
3254553	NM_080669.6(SLC46A1):c.1253del (p.Leu418fs)	Pathogenic
850	NM_080669.6(SLC46A1):c.1082-1G>A	Pathogenic
854	NM_080669.6(SLC46A1):c.1126C>T (p.Arg376Trp)	Pathogenic
1701314	NM_080669.6(SLC46A1):c.1322+2_1322+4delinsAT	Likely pathogenic
21743	NM_080669.6(SLC46A1):c.1274C>G (p.Pro425Arg)	Likely pathogenic
3255576	NM_080669.6(SLC46A1):c.1173_1174del (p.Ser393fs)	Likely pathogenic

SpliceAI

4299 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28367404:A:AC	donor_gain	1.0000
17:28367405:C:CC	donor_gain	1.0000
17:28367477:CTTGT:C	acceptor_gain	1.0000
17:28367482:C:CC	acceptor_gain	1.0000
17:28367709:TCCTA:T	donor_loss	1.0000
17:28367710:CCTA:C	donor_loss	1.0000
17:28367711:CTA:C	donor_loss	1.0000
17:28367712:TA:T	donor_loss	1.0000
17:28367712:TAC:T	donor_loss	1.0000
17:28367713:ACC:A	donor_loss	1.0000
17:28367716:T:TA	donor_gain	1.0000
17:28368056:CCAG:C	acceptor_gain	1.0000
17:28368057:CAG:C	acceptor_gain	1.0000
17:28368057:CAGC:C	acceptor_gain	1.0000
17:28368516:CATA:C	donor_loss	1.0000
17:28368519:AC:A	donor_loss	1.0000
17:28368870:AC:A	donor_gain	1.0000
17:28368871:CC:C	donor_gain	1.0000
17:28368893:C:CA	donor_gain	1.0000
17:28368906:G:C	donor_gain	1.0000
17:28368934:T:TA	donor_gain	1.0000
17:28369024:CTACC:C	acceptor_gain	1.0000
17:28369285:GCACC:G	donor_loss	1.0000
17:28369288:C:G	donor_loss	1.0000
17:28369306:T:TA	donor_gain	1.0000
17:28369307:C:A	donor_gain	1.0000
17:28369308:C:A	donor_gain	1.0000
17:28369424:CTGCC:C	acceptor_gain	1.0000
17:28369425:TGCC:T	acceptor_gain	1.0000
17:28369426:GCC:G	acceptor_gain	1.0000

AlphaMissense

4645 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28388236:T:C	F565L	1.000
17:28388238:C:A	F565L	1.000
17:28388238:C:G	F565L	1.000
17:28388367:T:C	L584P	1.000
17:28388423:T:C	F603L	1.000
17:28388425:C:A	F603L	1.000
17:28388425:C:G	F603L	1.000
17:28396158:T:A	W683R	1.000
17:28396158:T:C	W683R	1.000
17:28388240:T:A	I566N	0.999
17:28388242:A:C	S567R	0.999
17:28388244:C:A	S567R	0.999
17:28388244:C:G	S567R	0.999
17:28388352:T:C	L579P	0.999
17:28388390:T:C	F592L	0.999
17:28388392:C:A	F592L	0.999
17:28388392:C:G	F592L	0.999
17:28388424:T:G	F603C	0.999
17:28388448:T:A	V611D	0.999
17:28395918:C:A	A646D	0.999
17:28388234:T:A	V564D	0.998
17:28388237:T:C	F565S	0.998
17:28388245:T:G	Y568D	0.998
17:28388273:C:A	A577D	0.998
17:28388355:T:C	L580P	0.998
17:28388436:T:C	L607P	0.998
17:28388528:T:A	W638R	0.998
17:28388528:T:C	W638R	0.998
17:28388534:C:G	H640D	0.998
17:28395907:G:C	E642D	0.998

dbSNP variants (sampled 300 via entrez): RS1000124505 (17:28372365 G>A), RS1000219773 (17:28372695 T>C), RS1001214295 (17:28390865 A>C), RS1001300116 (17:28397956 C>T), RS1001548054 (17:28377263 A>C,G), RS1001607128 (17:28397663 C>A,G), RS1002226271 (17:28385138 T>C), RS1002456899 (17:28371700 C>T), RS1002924966 (17:28381328 G>T), RS1003062259 (17:28381620 G>A), RS1003260101 (17:28379791 G>C), RS1003488965 (17:28372839 C>G), RS1003506774 (17:28399256 C>A,G,T), RS1003604023 (17:28386621 A>T), RS1003659052 (17:28392714 G>A)

Disease associations

OMIM: gene MIM:607732 | disease phenotypes: MIM:616829, MIM:229050

GenCC curated gene-disease

Mondo (3): TMEM199-CDG (MONDO:0014790), hereditary folate malabsorption (MONDO:0009238), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (3): TMEM199-CDG (Orphanet:466703), Hereditary folate malabsorption (Orphanet:90045), Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0007354	Amyotrophic lateral sclerosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002546_2	Osteoprotegerin levels	1.000000e-09
GCST004692_7	Amyotrophic lateral sclerosis	1.000000e-08
GCST004901_3	Amyotrophic lateral sclerosis (sporadic)	3.000000e-10

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
C562799	Folate Malabsorption, Hereditary (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523350 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 269,611 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1140	NIACINAMIDE	4	231,688
CHEMBL1201022	PHENAZOPYRIDINE HYDROCHLORIDE	4	6,331
CHEMBL1201863	DEXLANSOPRAZOLE	4	1,583
CHEMBL1219	RABEPRAZOLE	4	12,441
CHEMBL869	NITROFURAZONE	4	13,461
CHEMBL1475252	TENATOPRAZOLE	2	2,247
CHEMBL12089	BERBERINE CHLORIDE	1	1,860

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

159 measured of 617 human assays (696 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-pyridin-3-yl-1H-pyridin-2-one	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2-fluoro-5-(4-methyl-3-pyridinyl)phenol	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
7-fluoro-6-(4-methyl-3-pyridinyl)-1H-indole-2,3-dione	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
1-[2-hydroxy-4-(4-methyl-3-pyridinyl)phenyl]ethanone	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2-amino-4-(4-methyl-3-pyridinyl)phenol	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
7-(4-methyl-3-pyridinyl)-4H-1,4-benzoxazin-3-one	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
5-(4-methyl-3-pyridinyl)-1H-pyrazolo[4,5-b]pyridine	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
5-(4-methyl-3-pyridinyl)-3H-1,3-benzoxazol-2-one	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
5-(4-methyl-3-pyridinyl)pyridin-3-ol	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
3-methyl-5-(4-methyl-3-pyridinyl)-1H-benzimidazol-2-one	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
7-chloro-5-(4-methyl-3-pyridinyl)-1H-indazole	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2-chloro-6-fluoro-4-(4-methyl-3-pyridinyl)phenol	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
7-(4-methyl-3-pyridinyl)-3,4-dihydro-1H-quinazolin-2-one	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(5-amino-3-pyridinyl)-3H-1,3-benzoxazol-2-one	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
8-(4-methyl-3-pyridinyl)-3,5-dihydro-2H-1,5-benzoxazepin-4-one	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
5-(4-methyl-3-pyridinyl)-3-(trifluoromethyl)-2H-indazole	IC50	0.55 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
3-pyridin-3-ylphenol	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
7-(4-methyl-3-pyridinyl)-3,4-dihydro-2H-isoquinolin-1-one	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(4-methyl-3-pyridinyl)-1H-indole	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
5-(4-methyl-3-pyridinyl)-2,3-dihydro-1H-indole	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
3-fluoro-4-(4-methyl-3-pyridinyl)benzene-1,2-diol	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
5-(4-methyl-3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(4-methyl-3-pyridinyl)-3,4-dihydro-2H-1,4-benzoxazine	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(4-methyl-3-pyridinyl)-1,3-dihydroindol-2-one	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(6-chloro-4-methyl-3-pyridinyl)-3H-1,3-benzoxazol-2-one	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(4,6-dimethyl-3-pyridinyl)-3H-1,3-benzoxazol-2-one	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2-[4-(4-methyl-3-pyridinyl)phenyl]guanidine	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
3-methyl-5-(4-methyl-3-pyridinyl)-1H-2lambda6,1,3-benzothiadiazole 2,2-dioxide	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(4-methyl-3-pyridinyl)quinazolin-2-amine	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
4-fluoro-5-(4-methyl-3-pyridinyl)-1H-indazole	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(5-methyl-2-oxo-1H-pyridin-4-yl)-3H-1,3-benzoxazol-2-one	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
7-fluoro-6-(4-methyl-3-pyridinyl)-3H-1,3-benzoxazol-2-one	IC50	50.5 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2-fluoro-4-(4-methyl-3-pyridinyl)phenol	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
3-fluoro-4-(4-methyl-3-pyridinyl)phenol	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
4-fluoro-3-(4-methyl-3-pyridinyl)phenol	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2-methyl-3-(4-methyl-3-pyridinyl)phenol	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2-chloro-3-(4-methyl-3-pyridinyl)phenol	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2-methoxy-4-(4-methyl-3-pyridinyl)phenol	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-fluoro-5-(4-methyl-3-pyridinyl)-1H-indole	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
2,6-difluoro-3-(4-methyl-3-pyridinyl)phenol	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(4-methyl-3-pyridinyl)-3,4-dihydro-1H-quinazolin-2-one	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
5-(4-methyl-3-pyridinyl)-1H-pyrazolo[3,4-c]pyridine	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
7-(4-methyl-3-pyridinyl)-3,4-dihydro-2H-1,4-benzoxazine	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
5-(4-methyl-3-pyridinyl)-1H-indazol-3-amine	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
6-(4-methylpyrimidin-5-yl)-3H-1,3-benzoxazol-2-one	IC50	208 nM	US-20250236613: SARM1 MODULATORS, PREPARATIONS, AND USES THEREOF
N-(3-cyclobutyl-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide	IC50	5500 nM	WO-2025054369: COMPOUNDS, COMPOSITIONS, AND METHODS
N-(3-(cyclopropylmethyl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide	IC50	5500 nM	WO-2025054369: COMPOUNDS, COMPOSITIONS, AND METHODS
N-(4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide	IC50	5500 nM	WO-2025054369: COMPOUNDS, COMPOSITIONS, AND METHODS
N-(4-methyl-3-(1-methylazetidin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide	IC50	5500 nM	WO-2025054369: COMPOUNDS, COMPOSITIONS, AND METHODS
N-(4-chloro-3-((1R,2S)-2-cyanocyclopropyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide	IC50	5500 nM	WO-2025054369: COMPOUNDS, COMPOSITIONS, AND METHODS

ChEMBL bioactivities

71 potent at pChembl≥5 of 85 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	Kd	12	nM	CHEMBL6143553
7.42	Kd	38	nM	CHEMBL6159835
7.41	Kd	39	nM	CHEMBL6162644
6.82	IC50	150	nM	CHEMBL2009370
6.80	IC50	158	nM	CHEMBL6160306
6.66	IC50	218	nM	CHEMBL6160306
6.64	IC50	228	nM	CHEMBL6164337
6.64	IC50	227	nM	CHEMBL6164337
6.62	IC50	242	nM	CHEMBL6142057
6.56	Kd	278	nM	CHEMBL6161497
6.54	IC50	288	nM	CHEMBL6162644
6.54	IC50	285	nM	CHEMBL6146508
6.52	IC50	300	nM	CHEMBL6146508
6.42	IC50	376	nM	CHEMBL6159835
6.42	IC50	385	nM	CHEMBL6152366
6.40	IC50	399	nM	CHEMBL6167847
6.40	IC50	402	nM	CHEMBL6162644
6.33	IC50	472	nM	CHEMBL6171204
6.30	IC50	496	nM	CHEMBL6171204
6.29	IC50	509	nM	CHEMBL6164481
6.24	IC50	574	nM	CHEMBL6159835
6.24	IC50	580	nM	CHEMBL6142057
6.23	IC50	588	nM	CHEMBL6167847
6.22	IC50	602	nM	CHEMBL6152713
6.16	IC50	700	nM	CHEMBL2009483
6.16	IC50	689	nM	CHEMBL6143553
6.14	IC50	718	nM	CHEMBL6144413
6.11	IC50	772	nM	CHEMBL6144413
6.10	IC50	796	nM	CHEMBL6148221
6.08	IC50	830	nM	CHEMBL6164481
6.04	IC50	917	nM	CHEMBL6152366
6.00	IC50	1010	nM	CHEMBL6150382
5.99	IC50	1020	nM	CHEMBL6152199
5.97	IC50	1070	nM	CHEMBL6148221
5.97	IC50	1080	nM	CHEMBL6159550
5.96	IC50	1100	nM	CHEMBL6152199
5.94	IC50	1160	nM	CHEMBL6152713
5.88	IC50	1320	nM	CHEMBL6170137
5.85	IC50	1420	nM	CHEMBL6165589
5.82	IC50	1530	nM	CHEMBL6165589
5.79	IC50	1610	nM	CHEMBL6168294
5.76	IC50	1730	nM	CHEMBL6143553
5.75	IC50	1770	nM	CHEMBL6159550
5.63	IC50	2340	nM	CHEMBL6148995
5.61	IC50	2460	nM	CHEMBL6151182
5.58	IC50	2600	nM	CHEMBL6167028
5.57	IC50	2720	nM	CHEMBL6161497
5.56	IC50	2750	nM	CHEMBL6149629
5.56	IC50	2750	nM	CHEMBL6160803
5.53	IC50	2940	nM	CHEMBL6160803

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
graphene oxide	increases expression	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
chloroacetaldehyde	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Acrolein	increases abundance, affects cotreatment, decreases expression	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cisplatin	decreases expression	1
Oxygen	decreases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tunicamycin	increases expression	1
Urethane	decreases expression	1
2,4-Dichlorophenoxyacetic Acid	decreases expression	1
Cyclosporine	decreases expression	1

ChEMBL screening assays

25 unique, capped per target: 25 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4422579	Binding	Inhibition of StrepTag-tagged human SARM1 TIR (561 to 724 residues) expressed in HEK293T cells assessed as reduction in NADase activity in presence of NAD+ incubated for 60 mins by HPLC analysis	INHIBITORS OF SARM1 NADase ACTIVITY AND USES THEREOF

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS