Protein / target

Melanocortin receptor 4

Encoded byMC4RP32245Homo sapiensSwiss-Prot

UniProt: P32245 Ensembl: ENSG00000166603 HGNC: HGNC:6932 NCBI Gene: 4160

Clinically validated

Therapeutic maturity

Approved medicines

Open Targets target-level

View by indication →

Clinical trials

Small-molecule tractable

Druggability

Advanced Clinical

Protein at a glance

Biological role

Melanocyte-stimulating hormone receptor

Strongest disease association

Obesity disorder

Via encoding gene MC4R · Genetic evidence · score 0.91

Therapeutic position

Established drug target

Small molecules

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function overview

G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor.

View complete UniProt function annotation

G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor (PubMed:12646665, PubMed:14764818, PubMed:25163632, PubMed:32327598, PubMed:33858992, PubMed:8392067). Functions as a central component of the leptin-melanocortin pathway, which is essential for maintaining energy homeostasis (PubMed:32327598, PubMed:33858992). Upon activation, couples to G(s) protein, stimulating adenylate cyclase and the cAMP-dependent signaling pathway, which promotes anorexogenic signaling in the hypothalamus and contributes to a negative energy balance (PubMed:12588803, PubMed:14764818, PubMed:25163632, PubMed:33858992). Regulates food intake: activation by agonists suppresses appetite, whereas the antagonist Agouti-related protein/AGRP precludes agonist-induced signaling, thereby stimulating appetite (PubMed:9311920, PubMed:29311635). Modulates the firing activity of neurons in paraventricular nucleus (PVN) of the hypothalamus via alpha-MSH and AGRP regulation of inwardly rectifying potassium channel KCNJ13 closure, independently of G(s) signaling (PubMed:32327598). In the PVN, also interacts with opsin 3/OPN3, which couples to G(i/o) proteins to inhibit MC4R-mediated cAMP signaling, thereby promoting food intake (PubMed:39951488). In intestinal epithelial cells, contributes to inhibition of hepatic glucose production via nesfatin-1/NUCB2, leading to increased cAMP levels and glucagon-like peptide 1 (GLP-1) secretion (PubMed:39562740). Interaction with MGRN1 displaces the G(s) protein, further decreasing MC4R signaling activity (PubMed:19737927). Also activated by gamma-MSH, though with low potency (PubMed:8392067)

Subcellular location

Cell membraneCell projection, cilium membrane

Domains and Gene Ontology detail (18)

Gene Ontology

Ccytoplasm
Cmembrane
Cnon-motile cilium membrane
Cplasma membrane
Fcorticotropin receptor activity
Fmelanocortin receptor activity
Fmelanocyte-stimulating hormone receptor activity
Fneuropeptide binding
Fubiquitin protein ligase binding
Padenylate cyclase-activating G protein-coupled receptor signaling pathway
Padenylate cyclase-modulating G protein-coupled receptor signaling pathway
Pfeeding behavior

332 aa · 37 kDa

Biological roles

Reactome v97

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

G protein-coupled signallingUniProt · GO

View supporting evidence

G protein-coupled signalling

·G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-M…
·adenylate cyclase-activating G protein-coupled receptor signaling pathway
·adenylate cyclase-modulating G protein-coupled receptor signaling pathway

View underlying pathways (3)

Peptide ligand-binding receptors

G alpha (s) signalling events

Transcriptional and post-translational regulation of MITF-M expression and activity

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Interaction neighbourhood

STRING v12.0

Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.

10 strongest partners — larger node and heavier line mean higher confidence

Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.

Approved medicines with mapped indications

1 medicine · 1 area

Approved therapies targeting this protein, grouped by what they are approved to treat — the disease-first view of the medicines below. Relationships come from the canonical approved-indication graph (ChEMBL phase-4), the same source as the drug cards.

Obesity1 medicine

setmelanotide

4 medicines meet Open Targets' target-level approved-medicine definition; the 1 shown here are those on this page with a canonical approved disease indication in the graph. Approved indications from ChEMBL (phase-4), via the canonical drug→disease graph.

Drugs targeting this protein

How approved and investigational drugs engage this protein — mechanism and action type, direct vs complex targeting, and how broadly each acts across other targets. A drug-first view (the section above groups the approved ones disease-first); direct binders with few recorded targets are listed first.

setmelanotide

Narrow target profileApprovedAgonist

Melanocortin receptor 4 agonist

Indicated for Obesity

Direct interaction with this protein · Only this protein recorded as a target

ChEMBL mechanism, action type, target identity and approved indications. Open Targets clinical status.

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene MC4R

Gene-level evidence surfaced through the gene MC4Rthat encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Obesity disorder

0.98Well supported

Genetic evidence dominant · Open Targets 0.79

Obesity due to melanocortin 4 receptor deficiency

0.91Well supported

Genetic evidence dominant · Open Targets 0.69

Diabetes Mellitus, Type 2

0.81Well supported

Genetic evidence dominant · Open Targets 0.51

Metabolic Syndrome

0.81Well supported

Genetic evidence dominant · Open Targets 0.46

Diabetes Mellitus

0.78Well supported

Genetic evidence dominant · Open Targets 0.48

View evidence synthesis (5)

Obesity disorderWell supported

0.98

agreement 0.89–1.00

Genetic44%Clinical32%Animal model18%Literature7%Genetic literaturedup

Open Targets aggregate 0.79 · 4 independent evidence families · 1 not counted as duplicate

Obesity due to melanocortin 4 receptor deficiencyWell supported

0.91

agreement 0.79–1.00

Genetic60%Animal model29%Literature11%

Open Targets aggregate 0.69 · 3 independent evidence families

Diabetes Mellitus, Type 2Well supported

0.81

agreement 0.68–0.95

Genetic85%Literature15%

Open Targets aggregate 0.51 · 2 independent evidence families

Metabolic SyndromeWell supported

0.81

agreement 0.69–0.93

Genetic64%Animal model27%Literature9%

Open Targets aggregate 0.46 · 3 independent evidence families

Diabetes MellitusWell supported

0.78

agreement 0.64–0.92

Genetic92%Literature8%

Open Targets aggregate 0.48 · 2 independent evidence families

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the per-type scores above show the calculation.

Show all associations

Obesity disorder0.79

Obesity due to melanocortin 4 receptor deficiency0.69

Diabetes Mellitus, Type 20.51

Sexual dysfunction0.49

Bardet-Biedl Syndrome0.49

Diabetes Mellitus0.48

Metabolic Syndrome0.46

Overnutrition0.43

Drug development

5 compounds recorded · 4 approved · 1 in clinical development

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines. Distinct from the 1 drug that targets this protein in Forefront's canonical graph (1 with a mapped approved indication, shown above): these count different sets and are not a subset relation.

View all recorded compounds (5)

BREMELANOTIDEApproval

BREMELANOTIDE ACETATEApproval

SETMELANOTIDE ACETATEApproval

SETMELANOTIDEApproval

PF-00446687Phase 2

Open Targets known-drugs universe. Drug name and highest clinical stage only — the disease relationship is NOT read from this slice (it carries trial-context noise); approved indications come from the canonical graph above.

Tractability

Small molecules — Strong

Advanced Clinical and Structure with Ligand support this modality.

Antibodies — Emerging

Feasibility evidence (uniprot loc high conf and go cc high conf) — no clinical-stage drug of this modality recorded.

Protein degraders — Emerging

Feasibility evidence (small molecule binder) — no clinical-stage drug of this modality recorded.

Other modalities — Strong

Approved Drug support this modality.

View underlying tractability evidence (9)

SM · Advanced ClinicalSM · Structure with LigandSM · High-Quality LigandSM · Druggable FamilyAB · UniProt loc high confAB · GO CC high confAB · UniProt SigP or TMHMMPR · Small Molecule BinderOC · Approved Drug

Raw Open Targets tractability assessment buckets, by modality.

Safety-related annotations

weight gainClinPGx

Terms indexed against this target in Open Targets' safety data, with their datasource. These are annotations, not causal claims: the direction of effect (whether activation or inhibition is implicated), species and evidence strength are not captured here, so an entry does not mean that modulating this target is known to cause that condition.

Clinical trials

Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein. Ranked by active status, then clinical phase and recency, and spread across the targeting drugs.

Real-World Effectiveness, Safety and Patient-reported Outcomes of Setmelanotide in Patients With Bardet-Biedl Syndrome: A Prospective Mono Centric Observational Interventional StudyPHASE4

RECRUITING · via setmelanotide · NCT07674290

A Phase 3, Double Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Setmelanotide in Patients With Acquired Hypothalamic ObesityPHASE3

RECRUITING · via setmelanotide · NCT06760546

Open-Label Extension Study of Setmelanotide in Patients With a Rare Genetic, Syndromic or Acquired Disease of the MC4R PathwayPHASE3

ENROLLING_BY_INVITATION · via setmelanotide · NCT06596135

A Phase 3, Double Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Setmelanotide in Patients With Acquired Hypothalamic ObesityPHASE3

ACTIVE_NOT_RECRUITING · via setmelanotide · NCT05774756

View all trials (18)

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial: Multiple Independent Sub-studies of Setmelanotide in Patients With POMC/PCSK1, LEPR, NCOA1(SRC1), or SH2B1 Gene Variants in the Melanocortin-4 Receptor PathwayPHASE3

ACTIVE_NOT_RECRUITING · via setmelanotide · NCT05093634

Setmelanotide to Treat Obesity in a Patient With Pseudohypoparathyroidism Type 1a (PHP1a)PHASE2

NOT_YET_RECRUITING · via setmelanotide · NCT07496463

A Phase 2 Open-label Study of Setmelanotide in Patients With Prader-Willi SyndromePHASE2

ACTIVE_NOT_RECRUITING · via setmelanotide · NCT06772597

A Randomized, Double-Blind, 3-arm, Parallel Group, Placebo- and Positive-controlled Study to Investigate the Effects of Setmelanotide on QTc Interval in Healthy SubjectsPHASE4

COMPLETED · via setmelanotide · NCT05046132

A Phase 3 Multi-Center, 1-Year, Open-Label Study of Setmelanotide in Pediatric Patients Aged 2 to <6 Years of Age With Rare Genetic Causes of ObesityPHASE3

COMPLETED · via setmelanotide · NCT04966741

A Phase 3, Randomized, Double-Blind Trial of Two Formulations of Setmelanotide (Daily and Weekly) With a Crossover to Open-Label Once Weekly Setmelanotide in Patients With Specific Gene Defects in the Melanocortin-4 Receptor Pathway Who Are Currently on a Stable Dose of the Once Daily FormulationPHASE3

COMPLETED · via setmelanotide · NCT05194124

A Phase 3 Trial of Setmelanotide (RM-493), a Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Patients With Moderate to Severe ObesityPHASE3

COMPLETED · via setmelanotide · NCT03746522

Long Term Extension Trial of Setmelanotide (RM-493) for Patients Who Have Completed a Trial of Setmelanotide for the Treatment of Obesity Associated With Genetic Defects Upstream of the MC4 Receptor in the Leptin-melanocortin PathwayPHASE2/PHASE3

COMPLETED · via setmelanotide · NCT03651765

An Open Label, 1-Year Trial, Including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Leptin Receptor (LEPR) Deficiency Obesity Due to Bi-Allelic Loss-of-Function LEPR Genetic MutationPHASE3

COMPLETED · via setmelanotide · NCT03287960

An Open-Label, 1-Year Trial, Including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Early Onset POMC Deficiency Obesity Due to Bi-Allelic Loss-of-Function POMC or PCSK1 Genetic MutationPHASE3

COMPLETED · via setmelanotide · NCT02896192

A 2-Stage (Open-Label Followed by Randomized Double-Blind, Placebo-Controlled Stage), Phase 2 Trial of Setmelanotide in Patients With Specific Gene Variants in the Melanocortin-4 Receptor PathwayPHASE2

COMPLETED · via setmelanotide · NCT04963231

A Phase 2, Open-Label 20-Week Study to Evaluate the Safety and Efficacy of Setmelanotide in Subjects With Hypothalamic ObesityPHASE2

COMPLETED · via setmelanotide · NCT04725240

Expanded-access for the Use of Setmelanotide in a Single Patient With Partial Lipodystrophy (LD) Associated With Leptin Deficiency and Multiple Autoimmune DiseasesPHASE2

COMPLETED · via setmelanotide · NCT03262610

Setmelanotide (RM-493) Phase 2 Treatment Trial in Patients With Rare Genetic Disorders of ObesityPHASE2

COMPLETED · via setmelanotide · NCT03013543

A Phase 2, Randomized, Double-Blind, Placebo-controlled Pilot Study to Assess the Effects of RM-493, a Melanocortin 4 Receptor (MC4R) Agonist, in Obese Subjects With Prader-Willi Syndrome (PWS) on Safety, Weight Reduction, and Food-Related BehaviorsPHASE2

COMPLETED · via setmelanotide · NCT02311673

A Staged, Phase 1b/Phase 2a, Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety and Efficacy of RM-493, a Melanocortin 4 Receptor (MC4R) Agonist in Obese Patients Using a Once or Twice Daily Sub-Cutaneous Injection FormulationPHASE1/PHASE2

COMPLETED · via setmelanotide · NCT02041195

A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of RM-493, a Melanocortin 4 Receptor (MC4R) Agonist in Obese PatientsPHASE2

COMPLETED · via setmelanotide · NCT01749137

A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Setmelanotide in Subjects With Varying Degrees of Renal ImpairmentPHASE1

COMPLETED · via setmelanotide · NCT04348175

ClinicalTrials.gov via the drug-target graph.

What's happening now

Recent therapeutic activity around this target — regulatory actions, clinical trials and safety signals for a drug that targets this protein, plus publications where such a drug is a genuine subject. Every item is reached indirectly through the drug, not the protein itself; incidental mentions (a paper that merely measures a drug) and press items are excluded.

Regulatory approval2021-07-16
Approval: Imcivree (EMA)
ema · regulatory · ema · via setmelanotide

Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.