SMPD1

Sphingomyelin phosphodiesterase 1

Score: 0.528 Price: $0.53 Medium Druggability Status: active Wiki: SMPD1

🧠 Neurodegeneration

HYPOTHESES

1

PAPERS

0

KG EDGES

63

DEBATES

0

3D Protein Structure

🧬 SMPD1 — PDB 5FI9 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.47

Clinical Stage

Approved

Target Class

Enzyme

Safety

0.40

Druggability Analysis

Drug Development0.75

Structural Tractability0.70

Target Class0.85

Safety Profile0.40

Key Metrics

PDB Structures:

8

Known Drugs:

1

Approved:

1

In Clinical Trials:

0

Drug Pipeline (1 compounds)

1 Approved

Therapeutic Areas:

Niemann-Pick disease (types A, B, C) Neuroinflammation and neurodegeneration Lysosomal storage disorders Ceramide-mediated apoptotic pathways Alzheimer's disease (ceramide pathway) Parkinson's disease

Druggability Rationale: SMPD1 is moderately druggable (0.55 score) due to its well-characterized lysosomal enzyme class, defined active site architecture, and successful precedent with Olipudase alfa (approved enzyme replacement therapy). However, the medium druggability score reflects challenges in achieving selective small-molecule inhibition of sphingomyelinase activity while avoiding off-target effects on related phosphodiesterases and navigating lysosomal delivery constraints.

Mechanism: Small molecule inhibitor or modulator of sphingomyelinase activity

Drug Pipeline (1 compounds)

1 Approved

Known Drugs:

Olipudase alfa (approved) — Niemann-Pick disease type A and B

Structural Data:

PDB (8) ✓AlphaFold ✓Cryo-EM —

5FI9 5FIB 5FIC 5HQN 5I81+3 more

UniProt: E9LUE7

Binding Pocket Analysis:

The active site is a well-defined catalytic pocket typical of zinc-dependent phosphodiesterases, with high-resolution structural data available (best resolution 2.25 Å across 5 PDB structures). The pocket accommodates sphingomyelin substrate and presents opportunities for selective inhibitor design through targeting substrate-binding sub-pockets and allosteric sites distant from the catalytic zinc center.

Selectivity & Safety Considerations

Selectivity is a significant challenge given the structural homology between SMPD1 and related sphingomyelinases (SMPD2, SMPD3), requiring ligand design to exploit subtle active-site differences. Additionally, off-target inhibition of other lysosomal phosphodiesterases must be carefully managed to minimize unintended metabolic disruption.

3D Protein Structure

PDB: Open in RCSB AlphaFold model

Interactive 3D viewer powered by RCSB PDB / Mol*. Use mouse to rotate, scroll to zoom.

Clinical Trials (7)

Relevant trials from ClinicalTrials.gov

Active

1

Completed

5

Total Enrollment

134

By Phase

PHASE1: 1 · PHASE2: 3 · Unknown: 3

A Real-world Long-term Safety and Immunogenicity Study of Olipudase Alfa Therapy in Pediatric Patients Less Than 2 Years Recruiting

Unknown NCT06192576 n=10

Niemann-Pick Diseases, Acid Sphingomyelinase Deficiency

Interventions: Olipudase alfa

Sponsor: Sanofi | Started: 2024-04-16

Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase D Completed

PHASE2 NCT02004691 n=36

Sphingomyelin Lipidosis

Interventions: placebo (saline), Olipudase alfa

Sponsor: Genzyme, a Sanofi Company | Started: 2015-12-18

A Long-Term Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency Completed

PHASE2 NCT02004704 n=25

Sphingomyelin Lipidosis

Interventions: GZ402665

Sponsor: Genzyme, a Sanofi Company | Started: 2013-12-04

A Study to Evaluate Safety and Tolerability of Olipudase Alfa in Pediatric and Adult Participants With Acid Sphingomyeli Completed

PHASE2 NCT06949358 n=3

Niemann-Pick Disease

Interventions: Olipudase alfa

Sponsor: Sanofi | Started: 2021-11-18

Safety, Tolerability, PK, and Efficacy Evaluation of Repeat Ascending Doses of Olipudase Alfa in Pediatric Patients <18 Completed

PHASE1 NCT02292654 n=20

Sphingomyelin Lipidosis

Interventions: Olipudase alfa

Sponsor: Genzyme, a Sanofi Company | Started: 2015-05-01

Data Analysis of Adult and Pediatric Participants With Acid Sphingomyelinase Deficiency (ASMD) on Early Access to Olipud Completed

Unknown NCT05359276 n=40

Acid Sphingomyelinase Deficiency (ASMD)

Interventions: Olipudase alfa

Sponsor: Sanofi | Started: 2022-06-10

Compassionate Use Program for Olipudase Alfa Enzyme Replacement Therapy for Patients With Chronic Acid Sphingomyelinase Approved For Marketing

Unknown NCT04877132

Sphingomyelin Lipidosis

Interventions: olipudase alfa (GZ402665)

Sponsor: Sanofi

Linked Hypotheses (3)

Selective Acid Sphingomyelinase Modulation Therapy0.648

TREM2-ASM Crosstalk in Microglial Lysosomal Senescence0.612

Senescent Cell ASM-Complement Cascade Intervention0.552

Linked Experiments (0)

No linked experiments

Scoring Dimensions

Knowledge Graph (20)

associated with (8)

SMPD1 → neurodegeneration

SMPD1 → SLC17A5

...and 3 more

co discussed (4)

SMPD1 → CERS2

SMPD1 → SGMS1

contributes to (2)

SMPD1 → LRRK2

expressed in (3)

SMPD1 → "middle temporal gyrus"_spiny_L3

SMPD1 → "middle temporal gyrus"_aspiny_L3

SMPD1 → "middle temporal gyrus"_spiny_L5

implicated in (1)

SMPD1 → neurodegeneration

modifies (1)

SMPD1 → ceramide_biosynthesis

participates in (1)

SMPD1 → Acid sphingomyelinase / ceramide signaling

Debate History (0)

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