Inhibitors of membranous adenylyl cyclases

Roland Seifert; Gerald H. Lushington; Tung Chung Mou; Andreas Gille; Stephen R. Sprang

doi:10.1016/j.tips.2011.10.006

Inhibitors of membranous adenylyl cyclases

Roland Seifert
, Gerald H. Lushington
, Tung Chung Mou
, Andreas Gille
, Stephen R. Sprang

Division of Biological and Biomedical Sciences

Research output: Contribution to journal › Review article › peer-review

89 Scopus citations

Abstract

Membranous adenylyl cyclases (mACs) constitute a family of nine isoforms with different expression patterns. Studies with mAC gene knockout mice provide evidence for the notion that AC isoforms play distinct (patho)physiological roles. Consequently, there is substantial interest in the development of isoform-selective mAC inhibitors. Here, we review the current literature on mAC inhibitors. Structurally diverse inhibitors targeting the catalytic site and allosteric sites (e.g. the diterpene site) have been identified. The catalytic site of mACs accommodates both purine and pyrimidine nucleotides, with a hydrophobic pocket constituting a major affinity-conferring domain for substituents at the 2′- and 3′-O-ribosyl position of nucleotides. BODIPY-forskolin stimulates ACs 1 and 5 but inhibits AC2. However, so far, no inhibitor has been examined at all mAC isoforms, and data obtained with mAC inhibitors in intact cells have not always been interpreted cautiously enough. Future strategies for the development of the mAC inhibitor field are discussed critically.

Original language	English
Pages (from-to)	64-78
Number of pages	15
Journal	Trends in Pharmacological Sciences
Volume	33
Issue number	2
DOIs	https://doi.org/10.1016/j.tips.2011.10.006
State	Published - Feb 2012

Funding

We thank Drs Anshuman Dixit, Sara Dizayee, Michael B. Doughty, Stefan Dove, Michael Egger, Miriam Erdorf, Jens Geduhn, Martin Göttle, Jian-Xin Guo, Stefan Herzig, Klaus Höcherl, Roger A. Johnson, Melanie Hübner, Volkhard Kaever, Burkhard König, Prantik Maity, Jan Matthes, Cibele Pinto, Mark Richter, Dennis Rottländer, Michael Schäferling, Jennifer Schmidt, Yuequan Shen, Christian Spangler, Corinna Spangler, Philip Steindel, Srividya Suryanarayana, Hesham Taha, Stephen F. Vatner, Wei-Jen Tang, Jenna Wang, Jay J-Q. Wu and Qi-Yuan Zhang for collaboration on various aspects of the adenylyl cyclase project. We thank Jörg Bräunig and Annette Stanke for critical reading of the manuscript. We are also appreciative of the constructive critique of the reviewers. The mAC inhibitor project was supported by grants of the American Heart Association (AHA 005140Z, AHA 0450120Z) and Deutsche Forschungsgemeinschaft (Se 529/5-1, Se529/5-2) to R.S. and The National Institutes of Health (DK46371) to S.R.S.

Funders	Funder number
DK46371
P20GM103546
American Heart Association	AHA 005140Z, AHA 0450120Z
Se 529/5-1, Se529/5-2

Access to Document

10.1016/j.tips.2011.10.006

Cite this

@article{924aa6b072c1453fb3735a70205e7ddd,

title = "Inhibitors of membranous adenylyl cyclases",

abstract = "Membranous adenylyl cyclases (mACs) constitute a family of nine isoforms with different expression patterns. Studies with mAC gene knockout mice provide evidence for the notion that AC isoforms play distinct (patho)physiological roles. Consequently, there is substantial interest in the development of isoform-selective mAC inhibitors. Here, we review the current literature on mAC inhibitors. Structurally diverse inhibitors targeting the catalytic site and allosteric sites (e.g. the diterpene site) have been identified. The catalytic site of mACs accommodates both purine and pyrimidine nucleotides, with a hydrophobic pocket constituting a major affinity-conferring domain for substituents at the 2′- and 3′-O-ribosyl position of nucleotides. BODIPY-forskolin stimulates ACs 1 and 5 but inhibits AC2. However, so far, no inhibitor has been examined at all mAC isoforms, and data obtained with mAC inhibitors in intact cells have not always been interpreted cautiously enough. Future strategies for the development of the mAC inhibitor field are discussed critically.",

author = "Roland Seifert and Lushington, \{Gerald H.\} and Mou, \{Tung Chung\} and Andreas Gille and Sprang, \{Stephen R.\}",

note = "Funding Information: We thank Drs Anshuman Dixit, Sara Dizayee, Michael B. Doughty, Stefan Dove, Michael Egger, Miriam Erdorf, Jens Geduhn, Martin G{\"o}ttle, Jian-Xin Guo, Stefan Herzig, Klaus H{\"o}cherl, Roger A. Johnson, Melanie H{\"u}bner, Volkhard Kaever, Burkhard K{\"o}nig, Prantik Maity, Jan Matthes, Cibele Pinto, Mark Richter, Dennis Rottl{\"a}nder, Michael Sch{\"a}ferling, Jennifer Schmidt, Yuequan Shen, Christian Spangler, Corinna Spangler, Philip Steindel, Srividya Suryanarayana, Hesham Taha, Stephen F. Vatner, Wei-Jen Tang, Jenna Wang, Jay J-Q. Wu and Qi-Yuan Zhang for collaboration on various aspects of the adenylyl cyclase project. We thank J{\"o}rg Br{\"a}unig and Annette Stanke for critical reading of the manuscript. We are also appreciative of the constructive critique of the reviewers. The mAC inhibitor project was supported by grants of the American Heart Association (AHA 005140Z, AHA 0450120Z) and Deutsche Forschungsgemeinschaft (Se 529/5-1, Se529/5-2) to R.S. and The National Institutes of Health (DK46371) to S.R.S.",

year = "2012",

month = feb,

doi = "10.1016/j.tips.2011.10.006",

language = "English",

volume = "33",

pages = "64--78",

journal = "Trends in Pharmacological Sciences",

issn = "0165-6147",

publisher = "Elsevier Ltd",

number = "2",

}

TY - JOUR

T1 - Inhibitors of membranous adenylyl cyclases

AU - Seifert, Roland

AU - Lushington, Gerald H.

AU - Mou, Tung Chung

AU - Gille, Andreas

AU - Sprang, Stephen R.

N1 - Funding Information: We thank Drs Anshuman Dixit, Sara Dizayee, Michael B. Doughty, Stefan Dove, Michael Egger, Miriam Erdorf, Jens Geduhn, Martin Göttle, Jian-Xin Guo, Stefan Herzig, Klaus Höcherl, Roger A. Johnson, Melanie Hübner, Volkhard Kaever, Burkhard König, Prantik Maity, Jan Matthes, Cibele Pinto, Mark Richter, Dennis Rottländer, Michael Schäferling, Jennifer Schmidt, Yuequan Shen, Christian Spangler, Corinna Spangler, Philip Steindel, Srividya Suryanarayana, Hesham Taha, Stephen F. Vatner, Wei-Jen Tang, Jenna Wang, Jay J-Q. Wu and Qi-Yuan Zhang for collaboration on various aspects of the adenylyl cyclase project. We thank Jörg Bräunig and Annette Stanke for critical reading of the manuscript. We are also appreciative of the constructive critique of the reviewers. The mAC inhibitor project was supported by grants of the American Heart Association (AHA 005140Z, AHA 0450120Z) and Deutsche Forschungsgemeinschaft (Se 529/5-1, Se529/5-2) to R.S. and The National Institutes of Health (DK46371) to S.R.S.

PY - 2012/2

Y1 - 2012/2

N2 - Membranous adenylyl cyclases (mACs) constitute a family of nine isoforms with different expression patterns. Studies with mAC gene knockout mice provide evidence for the notion that AC isoforms play distinct (patho)physiological roles. Consequently, there is substantial interest in the development of isoform-selective mAC inhibitors. Here, we review the current literature on mAC inhibitors. Structurally diverse inhibitors targeting the catalytic site and allosteric sites (e.g. the diterpene site) have been identified. The catalytic site of mACs accommodates both purine and pyrimidine nucleotides, with a hydrophobic pocket constituting a major affinity-conferring domain for substituents at the 2′- and 3′-O-ribosyl position of nucleotides. BODIPY-forskolin stimulates ACs 1 and 5 but inhibits AC2. However, so far, no inhibitor has been examined at all mAC isoforms, and data obtained with mAC inhibitors in intact cells have not always been interpreted cautiously enough. Future strategies for the development of the mAC inhibitor field are discussed critically.

AB - Membranous adenylyl cyclases (mACs) constitute a family of nine isoforms with different expression patterns. Studies with mAC gene knockout mice provide evidence for the notion that AC isoforms play distinct (patho)physiological roles. Consequently, there is substantial interest in the development of isoform-selective mAC inhibitors. Here, we review the current literature on mAC inhibitors. Structurally diverse inhibitors targeting the catalytic site and allosteric sites (e.g. the diterpene site) have been identified. The catalytic site of mACs accommodates both purine and pyrimidine nucleotides, with a hydrophobic pocket constituting a major affinity-conferring domain for substituents at the 2′- and 3′-O-ribosyl position of nucleotides. BODIPY-forskolin stimulates ACs 1 and 5 but inhibits AC2. However, so far, no inhibitor has been examined at all mAC isoforms, and data obtained with mAC inhibitors in intact cells have not always been interpreted cautiously enough. Future strategies for the development of the mAC inhibitor field are discussed critically.

UR - https://www.scopus.com/pages/publications/84856531711

U2 - 10.1016/j.tips.2011.10.006

DO - 10.1016/j.tips.2011.10.006

M3 - Review article

C2 - 22100304

AN - SCOPUS:84856531711

SN - 0165-6147

VL - 33

SP - 64

EP - 78

JO - Trends in Pharmacological Sciences

JF - Trends in Pharmacological Sciences

IS - 2

ER -

Inhibitors of membranous adenylyl cyclases

Abstract

Funding

Access to Document

Other files and links

Fingerprint

Cite this