The orally active melanocortin-4 receptor antagonist BL-6020/979

A promising candidate for the treatment of cancer cachexia

R. Dallmann, P. Weyermann, C. Anklin, M. Boroff, K. Bray-French, B. Cardel, I. Courdier-Fruh, H. Deppe, J. Dubach-Powell, M. Erb, R. H. Haefeli, M. Henneböhle, H. Herzner, M. Hufschmid, Daniel Marks, S. Nordhoff, M. Papp, C. Rummey, G. Santos, F. Schärer & 7 others H. Siendt, M. Soeberdt, L. T. Sumanovski, M. Terinek, C. Mondadori, N. Güven, A. Feurer

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Under physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i. e., food intake is decreased and energy expenditure is increased-a vicious combination leading to catabolism. Agouti-related protein (AgRP), the endogenous antagonist at the melanocortin-4 receptor (MC-4R), was found to increase food intake and to reduce energy expenditure. This qualifies MC-4R blockade as an attractive mode of action for the treatment of cachexia. Based on this rationale, a novel series of small-molecule MC-4R antagonists was designed, from which the orally active compound BL-6020/979 (formerly known as SNT207979) emerged as the first promising development candidate showing encouraging pre-clinical efficacy and safety properties which are presented here. Methods and results: BL-6020/979 is an orally available, selective and potent MC-4R antagonist with a drug-like profile. It increased food intake and decreased energy expenditure in healthy wild-type but not in MC-4R deficient mice. More importantly, it ameliorated cachexia-like symptoms in the murine C26 adenocarcinoma model; with an effect on body mass and body composition and on the expression of catabolic genes. Moreover, BL-6020/979 showed antidepressant-like properties in the chronic mild stress model in rats and exhibits a favorable safety profile. Conclusion: The properties of BL-6020/979 demonstrated in animal models and presented here make it a promising candidate suitable for further development towards a first-in-class treatment option for cachexia that potentially opens up the opportunity to treat two hallmarks of the disease, i. e., decreased food intake and increased energy expenditure, with one drug.

Original languageEnglish (US)
Pages (from-to)163-174
Number of pages12
JournalJournal of Cachexia, Sarcopenia and Muscle
Volume2
Issue number3
DOIs
StatePublished - Sep 2011

Fingerprint

Receptor, Melanocortin, Type 4
Cachexia
Energy Metabolism
Eating
Neoplasms
Agouti-Related Protein
Melanocortins
Safety
Body Composition
Pharmaceutical Preparations
Antidepressive Agents
Adenocarcinoma
Animal Models
Gene Expression

Keywords

  • C26 adenocarcinoma
  • Cancer cachexia
  • Food intake
  • Melanocortin-4 receptor antagonist
  • Metabolic rate
  • Mouse

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Physiology (medical)

Cite this

The orally active melanocortin-4 receptor antagonist BL-6020/979 : A promising candidate for the treatment of cancer cachexia. / Dallmann, R.; Weyermann, P.; Anklin, C.; Boroff, M.; Bray-French, K.; Cardel, B.; Courdier-Fruh, I.; Deppe, H.; Dubach-Powell, J.; Erb, M.; Haefeli, R. H.; Henneböhle, M.; Herzner, H.; Hufschmid, M.; Marks, Daniel; Nordhoff, S.; Papp, M.; Rummey, C.; Santos, G.; Schärer, F.; Siendt, H.; Soeberdt, M.; Sumanovski, L. T.; Terinek, M.; Mondadori, C.; Güven, N.; Feurer, A.

In: Journal of Cachexia, Sarcopenia and Muscle, Vol. 2, No. 3, 09.2011, p. 163-174.

Research output: Contribution to journalArticle

Dallmann, R, Weyermann, P, Anklin, C, Boroff, M, Bray-French, K, Cardel, B, Courdier-Fruh, I, Deppe, H, Dubach-Powell, J, Erb, M, Haefeli, RH, Henneböhle, M, Herzner, H, Hufschmid, M, Marks, D, Nordhoff, S, Papp, M, Rummey, C, Santos, G, Schärer, F, Siendt, H, Soeberdt, M, Sumanovski, LT, Terinek, M, Mondadori, C, Güven, N & Feurer, A 2011, 'The orally active melanocortin-4 receptor antagonist BL-6020/979: A promising candidate for the treatment of cancer cachexia', Journal of Cachexia, Sarcopenia and Muscle, vol. 2, no. 3, pp. 163-174. https://doi.org/10.1007/s13539-011-0039-1
Dallmann, R. ; Weyermann, P. ; Anklin, C. ; Boroff, M. ; Bray-French, K. ; Cardel, B. ; Courdier-Fruh, I. ; Deppe, H. ; Dubach-Powell, J. ; Erb, M. ; Haefeli, R. H. ; Henneböhle, M. ; Herzner, H. ; Hufschmid, M. ; Marks, Daniel ; Nordhoff, S. ; Papp, M. ; Rummey, C. ; Santos, G. ; Schärer, F. ; Siendt, H. ; Soeberdt, M. ; Sumanovski, L. T. ; Terinek, M. ; Mondadori, C. ; Güven, N. ; Feurer, A. / The orally active melanocortin-4 receptor antagonist BL-6020/979 : A promising candidate for the treatment of cancer cachexia. In: Journal of Cachexia, Sarcopenia and Muscle. 2011 ; Vol. 2, No. 3. pp. 163-174.
@article{25f7ae5d664b47928b91902ca70d1fe5,
title = "The orally active melanocortin-4 receptor antagonist BL-6020/979: A promising candidate for the treatment of cancer cachexia",
abstract = "Background: Under physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i. e., food intake is decreased and energy expenditure is increased-a vicious combination leading to catabolism. Agouti-related protein (AgRP), the endogenous antagonist at the melanocortin-4 receptor (MC-4R), was found to increase food intake and to reduce energy expenditure. This qualifies MC-4R blockade as an attractive mode of action for the treatment of cachexia. Based on this rationale, a novel series of small-molecule MC-4R antagonists was designed, from which the orally active compound BL-6020/979 (formerly known as SNT207979) emerged as the first promising development candidate showing encouraging pre-clinical efficacy and safety properties which are presented here. Methods and results: BL-6020/979 is an orally available, selective and potent MC-4R antagonist with a drug-like profile. It increased food intake and decreased energy expenditure in healthy wild-type but not in MC-4R deficient mice. More importantly, it ameliorated cachexia-like symptoms in the murine C26 adenocarcinoma model; with an effect on body mass and body composition and on the expression of catabolic genes. Moreover, BL-6020/979 showed antidepressant-like properties in the chronic mild stress model in rats and exhibits a favorable safety profile. Conclusion: The properties of BL-6020/979 demonstrated in animal models and presented here make it a promising candidate suitable for further development towards a first-in-class treatment option for cachexia that potentially opens up the opportunity to treat two hallmarks of the disease, i. e., decreased food intake and increased energy expenditure, with one drug.",
keywords = "C26 adenocarcinoma, Cancer cachexia, Food intake, Melanocortin-4 receptor antagonist, Metabolic rate, Mouse",
author = "R. Dallmann and P. Weyermann and C. Anklin and M. Boroff and K. Bray-French and B. Cardel and I. Courdier-Fruh and H. Deppe and J. Dubach-Powell and M. Erb and Haefeli, {R. H.} and M. Henneb{\"o}hle and H. Herzner and M. Hufschmid and Daniel Marks and S. Nordhoff and M. Papp and C. Rummey and G. Santos and F. Sch{\"a}rer and H. Siendt and M. Soeberdt and Sumanovski, {L. T.} and M. Terinek and C. Mondadori and N. G{\"u}ven and A. Feurer",
year = "2011",
month = "9",
doi = "10.1007/s13539-011-0039-1",
language = "English (US)",
volume = "2",
pages = "163--174",
journal = "Journal of Cachexia, Sarcopenia and Muscle",
issn = "2190-5991",
publisher = "Springer Verlag",
number = "3",

}

TY - JOUR

T1 - The orally active melanocortin-4 receptor antagonist BL-6020/979

T2 - A promising candidate for the treatment of cancer cachexia

AU - Dallmann, R.

AU - Weyermann, P.

AU - Anklin, C.

AU - Boroff, M.

AU - Bray-French, K.

AU - Cardel, B.

AU - Courdier-Fruh, I.

AU - Deppe, H.

AU - Dubach-Powell, J.

AU - Erb, M.

AU - Haefeli, R. H.

AU - Henneböhle, M.

AU - Herzner, H.

AU - Hufschmid, M.

AU - Marks, Daniel

AU - Nordhoff, S.

AU - Papp, M.

AU - Rummey, C.

AU - Santos, G.

AU - Schärer, F.

AU - Siendt, H.

AU - Soeberdt, M.

AU - Sumanovski, L. T.

AU - Terinek, M.

AU - Mondadori, C.

AU - Güven, N.

AU - Feurer, A.

PY - 2011/9

Y1 - 2011/9

N2 - Background: Under physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i. e., food intake is decreased and energy expenditure is increased-a vicious combination leading to catabolism. Agouti-related protein (AgRP), the endogenous antagonist at the melanocortin-4 receptor (MC-4R), was found to increase food intake and to reduce energy expenditure. This qualifies MC-4R blockade as an attractive mode of action for the treatment of cachexia. Based on this rationale, a novel series of small-molecule MC-4R antagonists was designed, from which the orally active compound BL-6020/979 (formerly known as SNT207979) emerged as the first promising development candidate showing encouraging pre-clinical efficacy and safety properties which are presented here. Methods and results: BL-6020/979 is an orally available, selective and potent MC-4R antagonist with a drug-like profile. It increased food intake and decreased energy expenditure in healthy wild-type but not in MC-4R deficient mice. More importantly, it ameliorated cachexia-like symptoms in the murine C26 adenocarcinoma model; with an effect on body mass and body composition and on the expression of catabolic genes. Moreover, BL-6020/979 showed antidepressant-like properties in the chronic mild stress model in rats and exhibits a favorable safety profile. Conclusion: The properties of BL-6020/979 demonstrated in animal models and presented here make it a promising candidate suitable for further development towards a first-in-class treatment option for cachexia that potentially opens up the opportunity to treat two hallmarks of the disease, i. e., decreased food intake and increased energy expenditure, with one drug.

AB - Background: Under physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i. e., food intake is decreased and energy expenditure is increased-a vicious combination leading to catabolism. Agouti-related protein (AgRP), the endogenous antagonist at the melanocortin-4 receptor (MC-4R), was found to increase food intake and to reduce energy expenditure. This qualifies MC-4R blockade as an attractive mode of action for the treatment of cachexia. Based on this rationale, a novel series of small-molecule MC-4R antagonists was designed, from which the orally active compound BL-6020/979 (formerly known as SNT207979) emerged as the first promising development candidate showing encouraging pre-clinical efficacy and safety properties which are presented here. Methods and results: BL-6020/979 is an orally available, selective and potent MC-4R antagonist with a drug-like profile. It increased food intake and decreased energy expenditure in healthy wild-type but not in MC-4R deficient mice. More importantly, it ameliorated cachexia-like symptoms in the murine C26 adenocarcinoma model; with an effect on body mass and body composition and on the expression of catabolic genes. Moreover, BL-6020/979 showed antidepressant-like properties in the chronic mild stress model in rats and exhibits a favorable safety profile. Conclusion: The properties of BL-6020/979 demonstrated in animal models and presented here make it a promising candidate suitable for further development towards a first-in-class treatment option for cachexia that potentially opens up the opportunity to treat two hallmarks of the disease, i. e., decreased food intake and increased energy expenditure, with one drug.

KW - C26 adenocarcinoma

KW - Cancer cachexia

KW - Food intake

KW - Melanocortin-4 receptor antagonist

KW - Metabolic rate

KW - Mouse

UR - http://www.scopus.com/inward/record.url?scp=84858992039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858992039&partnerID=8YFLogxK

U2 - 10.1007/s13539-011-0039-1

DO - 10.1007/s13539-011-0039-1

M3 - Article

VL - 2

SP - 163

EP - 174

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

SN - 2190-5991

IS - 3

ER -