TABLE 1.
List of compounds discovered by DS or DR approaches for SMA treatment.
| Molecular mechanism | Compound | Molecular class | DS/DR | Original target disease (for DR) | Clinical trial phase | Ref. And/or clinical trial |
|---|---|---|---|---|---|---|
| Direct and indirect modulation of SMN2 transcription | Branaplam (LMI070; NVS-101) | Pyridazine-derivative | DS | — | Active, not recruiting-phase II clinical trial for SMA | NCT02268552 |
| RG7800 (RO6885247) | Small molecule | DS | — | Stopped-phase I/II clinical trial for SMA | NCT02240355 | |
| Risdiplam (RG7916; RO7034067) | Small molecule (RG7800 derivative) | DS | — | Currently in phase II clinical trial for SMA | NCT02913482 (Firefish), NCT02908685 (Sunfish), NCT03032172 (Jewelfish), NCT03779334 (Rainbowfish), NCT04256265, NCT04177134 | |
| RG3039 (PF-06687859; D157495) | Quinazoline | DS | — | Suspended after phase I clinical trial for SMA | Gogliotti et al. (2013) | |
| Sodium vanadate | Inorganic sodium salt | DS | — | — | Liu et al. (2013) | |
| LDN-76070 | Small molecule | DS | — | — | Cherry et al. (2013) | |
| LDN-75654 | Small molecule | DS | — | — | Cherry et al. (2013) | |
| Brucea javanica | Simaroubaceae family’s medicinal plant | DS | — | — | Baek et al. (2019) | |
| Sodium butyrate | Organic sodium salt | DR | — | Recruiting-clinical trial for diabetes mellitus, type 1; several completed-trials (for shigellosis; gut health, SCFA metabolism, breast cancer, alcohol dependence, contact dermatitis, obesity) | Chang et al. (2001) | |
| Sodium phenylbutyrate | Sodium butyrate analogue | DR | Urea cycle disorder | FDA-approved | Andreassi et al. (2004) | |
| Completed-clinical trial in SMA | NCT00528268 (STOPSMA), NCT00439218 (NPTUNE02) and NCT00439569 (NPTUNE01) | |||||
| Valproic acid | Synthetic derivative of propylpentanoic acid | DR | Seizures; status epilepticus; bipolar disorder; migraine; schizophrenia | FDA-approved | Kissel et al. (2011) | |
| Completed-clinical trial in SMA | NCT00481013, NCT00374075 | |||||
| Trichostatin A (TSA) | Natural derivative of dienohydroxamic acid | DR | Mycosis | Recruiting-clinical trials for tumors, seizures, osteoarthritis, anemia, infertility, ischemic stroke, opioid dependence | Avila et al. (2007) | |
| Many completed-trials including infectious diseases | ||||||
| Vorinostat (suberoylanilide hydroxamic acid; SAHA) | Synthetic hydroxamic acid derivative | DS/DR | Cutaneous T-cell lymphoma | FDA-approved | Hahnen et al. (2006) | |
| Panobinostat (LHB589) | Cinnamic hydroxamic acid analogue | DR | Multiple myeloma | FDA-approved | Garbes et al. (2009) | |
| Celecoxib | Cyclo-oxygenase 2 inhibitor | DR | Osteoarthritis, rheumatoid arthritis in adults; juvenile arthritis; ankylosing spondylitis, colorectal polyps; pain; dysmenorrhea; cardiovascular risk reduction | FDA-approved | NCT02876094 | |
| Recruiting-phase II clinical trial for SMA | ||||||
| Hydroxyurea (Hydroxycarbamide) | Ribonucleoside diphosphate reductase inhibitor | DR | Chronic myelogenous leukemia; polycythemia vera; cervical, head, neck and ovarian cancers; melanoma; sickle cell anemia | FDA-approved | Grzeschik et al. (2005) | |
| Three completed-clinical trial for SMA | NCT00485511, NCT00568698, NCT00568802 | |||||
| Aclarubicin | Oligosaccharide anthracycline antineoplastic antibiotic | DS/DR | Acute myeloid leukemia | FDA-approved | Andreassi et al. (2001) | |
| Moxifloxacin | Synthetic fluoroquinolone antibiotic | DS/DR | Respiratory tract, skin and skin structure, intra-abdominal and GI infections, endocarditis, tuberculosis, nongonococcal urethritis, plague, meningitis and other CNS infections | FDA-approved | Konieczny and Artero (2020) | |
| Rigosertib | Synthetic benzyl styryl sulfone analogue | DS/DR | Chronic myelomonocytic leukemia | Currently in phase III clinical trial for chronic myelomonocytic leukemia | Son et al. (2019) | |
| NCT02562443 | ||||||
| Indoprofene (K4277) | Cyclooxygenase (COX) inhibitor | DS/DR | — | Recalled from the market | Kim et al. (2020) | |
| Cell death and degradation pathways | Levetiracetam (LEV; (S)-α-ethyl-2-oxo-pyrrolidine acetamide) | Pyrrolidine | DR | Seizures | FDA-approved | Ando et al. (2019) |
| NCT00324454 | ||||||
| Liuwei dihuang extract (LWDH) | Chinese herbal formula | DR | Kidneys, liver and asthma; geriatric diseases | — | Tseng et al. (2017) | |
| Bortezomib | Dipeptide boronic acid analogue | DR | Multiple myeloma | FDA-approved | Foran et al. (2016) | |
| Z-Phe-Ala fluoromethyle ketone (Z-FA-FMK) | Cysteine proteases irreversible inhibitor | DS | — | — | Wang et al. (2019) | |
| E64d | Cysteine protease inhibitor | DS | — | — | Wang et al. (2019) | |
| Edaravone | Pyrazolone | DR | Amyotrophic lateral sclerosis | FDA-approved | Sun et al. (2019) | |
| L-carnitine | Amino acid derivative | DR | Primary and secondary carnitine deficiency; end-stage renal disease | FDA-approved | Kissel et al. (2011) | |
| Completed phase II clinical trial for combinatorial treatment with valproic acid in SMA | NCT00227266, NCT00661453 | |||||
| Mitochondria-related pathways | Olesoxime (TRO19622) | Cholesterol-like structure | DR | Amyotrophic lateral sclerosis | Completed phase III clinical trial for ALS | Bordet et al. (2007) |
| Active, not recruiting-phase II clinical trial for SMA | NCT01302600, NCT02628743 | |||||
| Cytoskeleton dynamics, endocytic pathway and channel modulators | SRK-015 | Monoclonal antibody | — | — | Active, not recruiting-phase II clinical trial for SMA | NCT03921528 |
| Fasudil | Heterocyclic aromatic organic compound | DR | Cerebral vasospasm; cerebral ischemic symptoms | PMDA approved in Japan | Bowerman et al. (2012) | |
| Recruiting-phase II clinical trial for ALS | NCT03792490, eudra-CT-nr.: 2017-003676-31 | |||||
| Y-27632 | Rock inhibitor | — | — | — | Hensel et al. (2017) | |
| Fampiridine (Fampyra; 4 aminopyridine) | Aromatic amine | DS/DR | Multiple sclerosis | FDA-approved | Sleigh et al. (2011) | |
| Completed-phase III clinical trial in SMA | ||||||
| Reldesemtiv (CY 5021; CK-2127107) | Small molecule | DR | Chronic obstructive pulmonary disease; amyotrophic lateral sclerosis | Currently in phase II clinical trial for COPD; ALS and SMA | Ramdas and Servais (2020) | |
| NCT02644668 | ||||||
| Hormones signaling pathways | Somatotropin (growth hormone) | Hormone | DR | Chronic renal failure; turner and prader-Willi syndromes; growth disorders | FDA-approved pilot study for SMA | NCT00533221, NCT01369901 |
| Protirelin | Thyrotropin releasing hormone analogue | DR | Epilepsy; spinal cord injury; spinocerebellar ataxia; neonatal respiratory distress | FDA-approved | Tzeng et al. (2000) | |
| Taltirelin hydrate (TA-0910) | Thyrotropin releasing hormone analogue | DR | Spinocerebellar degeneration disease | Recruiting-phase IV clinical trial for SDD | Ohuchi et al., (2016) | |
| NCT0410774 | ||||||
| Prednisolone | Synthetic glucocorticoid | DR | Adrenocortical insufficiency; adrenogenital syndrome; hypercalcemia; thyroiditis; rheumatic, ocular, oral, hematologic disorders; collagen, dermatologic, lung, gastrointestinal, neoplastic and liver diseases; asthma; pericarditis; multiple sclerosis; myasthenia gravis¸ organ transplants; nephrotic syndrome | FDA-approved | Quattrocelli et al. (2017) | |
| Neurotransmitters' modulation | Riluzole | Benzothiazole derivative | DR | Amyotrophic lateral sclerosis | FDA-approved | Dimitriadi et al. (2013) |
| Completed phase III clinical trial for SMA | NCT00774423 (ASIRI) | |||||
| Ceftriaxone | Third generation cephalosporin antibiotic | DR | Acute otitis media; endocarditis; meningitis; septicemia; antibiotic prophylaxis; bone, joint, gastrointestinal, intra-abdominal, respiratory tract, skin and urinary tract infection | FDA-approved | Nizzardo et al. (2011) | |
| Lamotrigine | Synthetic phenyltriazine | DR | Lennox–Gastaut syndrome; bipolar disorder and mood episodes | FDA-approved | Nascimento et al. (2010) | |
| Gaboxadol hydrochloride | Synthetic compound | DS | — | — | Sleigh et al. (2011) | |
| Gabapentin | GABA chemical analogue | DR | Postherpetic neuralgia; partial-onset seizures; peripheral neuropathic pain; painful diabetic neuropathy | FDA-approved | Merlini et al. (2003) | |
| Two clinical trials completed on SMA type II and III patients | ||||||
| Neuromuscular junction stabilization | Amifampridine (pyridine-3,4-diamine, 3,4-diaminopyridine, 3,4-DAP) | Organic compound pyridine-derived | DR | Lambert-Eaton myasthenic syndrome (LEMS) | FDA-approved | NCT03781479, NCT03819660 |
| Recruiting-phase II for SMA | ||||||
| Tideglusib (NP-12, NP031112) | Small heterocyclic thiadiazolidine-based molecule | DS/DR | Alzheimer’s disease; progressive supranuclear palsy; congenital myotonic dystrophy | Completed phase II clinical trial for Alzheimer’s disease; | Makhortova et al. (2011) | |
| Not yet recruiting phase III clinical trial for congenital myotonic dystrophy | NCT03692312 | |||||
| Salbutamol (albuterol) | Selective beta2-adrenergic receptor agonist | DR | Asthma, chronic obstructive pulmonary disease | FDA-approved | Frongia et al. (2019) | |
| Recruiting-clinical trial for SMA in French register | NCT04177134 |
DR, drug repositioning; DS, drug screening; FDA, Food and Drug Administration; SMA, spinal muscular atrophy. Natural, chemical and FDA-approved compounds are classified by their mechanism of action. The SMA clinical study phases and the relative trial identifiers (NTC number from ClinicalTrials.gov) are indicated; when lacking, clinical trials referring to other pathologies, together with the most recent references to experimental SMA studies, are shown.