Target Information

Target General Information

Target ID

T51115 (Former ID: TTDS00414)

Target Name

Voltage-gated calcium channel alpha Cav1.2 (CACNA1C)

Synonyms

Voltage-gated calcium channel subunit alpha Cav1.2; Voltage-dependent L-type calcium channel subunit alpha-1C; Calcium channel, L type, alpha-1 polypeptide, isoform 1, cardiac muscle; CCHL1A1; CACNL1A1; CACN2; CACH2

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Gene Name

CACNA1C

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Alzheimer disease [ICD-11: 8A20]

Function

Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm. Plays an important role in excitation-contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm. Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.

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BioChemical Class

Voltage-gated ion channel

UniProt ID

CAC1C_HUMAN

Sequence

MVNENTRMYIPEENHQGSNYGSPRPAHANMNANAAAGLAPEHIPTPGAALSWQAAIDAAR
QAKLMGSAGNATISTVSSTQRKRQQYGKPKKQGSTTATRPPRALLCLTLKNPIRRACISI
VEWKPFEIIILLTIFANCVALAIYIPFPEDDSNATNSNLERVEYLFLIIFTVEAFLKVIA
YGLLFHPNAYLRNGWNLLDFIIVVVGLFSAILEQATKADGANALGGKGAGFDVKALRAFR
VLRPLRLVSGVPSLQVVLNSIIKAMVPLLHIALLVLFVIIIYAIIGLELFMGKMHKTCYN
QEGIADVPAEDDPSPCALETGHGRQCQNGTVCKPGWDGPKHGITNFDNFAFAMLTVFQCI
TMEGWTDVLYWVNDAVGRDWPWIYFVTLIIIGSFFVLNLVLGVLSGEFSKEREKAKARGD
FQKLREKQQLEEDLKGYLDWITQAEDIDPENEDEGMDEEKPRNMSMPTSETESVNTENVA
GGDIEGENCGARLAHRISKSKFSRYWRRWNRFCRRKCRAAVKSNVFYWLVIFLVFLNTLT
IASEHYNQPNWLTEVQDTANKALLALFTAEMLLKMYSLGLQAYFVSLFNRFDCFVVCGGI
LETILVETKIMSPLGISVLRCVRLLRIFKITRYWNSLSNLVASLLNSVRSIASLLLLLFL
FIIIFSLLGMQLFGGKFNFDEMQTRRSTFDNFPQSLLTVFQILTGEDWNSVMYDGIMAYG
GPSFPGMLVCIYFIILFICGNYILLNVFLAIAVDNLADAESLTSAQKEEEEEKERKKLAR
TASPEKKQELVEKPAVGESKEEKIELKSITADGESPPATKINMDDLQPNENEDKSPYPNP
ETTGEEDEEEPEMPVGPRPRPLSELHLKEKAVPMPEASAFFIFSSNNRFRLQCHRIVNDT
IFTNLILFFILLSSISLAAEDPVQHTSFRNHILFYFDIVFTTIFTIEIALKILGNADYVF
TSIFTLEIILKMTAYGAFLHKGSFCRNYFNILDLLVVSVSLISFGIQSSAINVVKILRVL
RVLRPLRAINRAKGLKHVVQCVFVAIRTIGNIVIVTTLLQFMFACIGVQLFKGKLYTCSD
SSKQTEAECKGNYITYKDGEVDHPIIQPRSWENSKFDFDNVLAAMMALFTVSTFEGWPEL
LYRSIDSHTEDKGPIYNYRVEISIFFIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNC
ELDKNQRQCVEYALKARPLRRYIPKNQHQYKVWYVVNSTYFEYLMFVLILLNTICLAMQH
YGQSCLFKIAMNILNMLFTGLFTVEMILKLIAFKPKGYFSDPWNVFDFLIVIGSIIDVIL
SETNHYFCDAWNTFDALIVVGSIVDIAITEVNPAEHTQCSPSMNAEENSRISITFFRLFR
VMRLVKLLSRGEGIRTLLWTFIKSFQALPYVALLIVMLFFIYAVIGMQVFGKIALNDTTE
INRNNNFQTFPQAVLLLFRCATGEAWQDIMLACMPGKKCAPESEPSNSTEGETPCGSSFA
VFYFISFYMLCAFLIINLFVAVIMDNFDYLTRDWSILGPHHLDEFKRIWAEYDPEAKGRI
KHLDVVTLLRRIQPPLGFGKLCPHRVACKRLVSMNMPLNSDGTVMFNATLFALVRTALRI
KTEGNLEQANEELRAIIKKIWKRTSMKLLDQVVPPAGDDEVTVGKFYATFLIQEYFRKFK
KRKEQGLVGKPSQRNALSLQAGLRTLHDIGPEIRRAISGDLTAEEELDKAMKEAVSAASE
DDIFRRAGGLFGNHVSYYQSDGRSAFPQTFTTQRPLHINKAGSSQGDTESPSHEKLVDST
FTPSSYSSTGSNANINNANNTALGRLPRPAGYPSTVSTVEGHGPPLSPAIRVQEVAWKLS
SNRERHVPMCEDLELRRDSGSAGTQAHCLLLRKANPSRCHSRESQAAMAGQEETSQDETY
EVKMNHDTEACSEPSLLSTEMLSYQDDENRQLTLPEEDKRDIRQSPKRGFLRSASLGRRA
SFHLECLKRQKDRGGDISQKTVLPLHLVHHQALAVAGLSPLLQRSHSPASFPRPFATPPA
TPGSRGWPPQPVPTLRLEGVESSEKLNSSFPSIHCGSWAETTPGGGGSSAARRVRPVSLM
VPSQAGAPGRQFHGSASSLVEAVLISEGLGQFAQDPKFIEVTTQELADACDMTIEEMESA
ADNILSGGAPQSPNGALLPFVNCRDAGQDRAGGEEDAGCVRARGRPSEEELQDSRVYVSS
L

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3D Structure

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AlphaFold

HIT2.0 ID

T77YFO

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

ARC029

Drug Info

Phase 3

Alzheimer disease

[2]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

R-56865

Drug Info

Terminated

Angina pectoris

[3]

SNAP-5089

Drug Info

Terminated

Heart arrhythmia

[4], [5]

TH-9229

Drug Info

Terminated

Reperfusion injury

[6]

Mode of Action

[+] 5 Modes of Action

Inhibitor

[+] 9 Inhibitor drugs

ARC029

Drug Info

[7]

CGS-27830

Drug Info

[8]

NIGULDIPINE

Drug Info

[1]

R-56865

Drug Info

[9]

SNAP-5089

Drug Info

[10]

CORYNANTHEINE

Drug Info

[1]

CV-4093

Drug Info

[7]

MEBUDIPINE

Drug Info

[15]

PD-32577

Drug Info

[16]

Modulator

[+] 2 Modulator drugs

TH-9229

Drug Info

[11]

CPU-228

Drug Info

[13]

Blocker (channel blocker)

[+] 1 Blocker (channel blocker) drugs

(-)-(R)-efonidipine

Drug Info

[12]

Activator

[+] 2 Activator drugs

(-)-(S)-BayK8644

Drug Info

[13]

FPL64176

Drug Info

[14]

Inhibitor (gating inhibitor)

[+] 3 Inhibitor (gating inhibitor) drugs

[3H](+)-cis-diltiazem

Drug Info

[17]

[3H](+)-isradipine

Drug Info

[18]

[3H](-)devapamil

Drug Info

[19]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: 1,3-Bis(bromomethyl)benzene

Ligand Info

Structure Description

CaV beta2a subunit: CaV1.2 AID-CEN complex

PDB:5V2Q

Method

X-ray diffraction

Resolution

1.70 Å

Mutation

Yes

[20]

PDB Sequence

ASPLEEDLCG

⁴³⁶

YLCWITQAE

Residue

Distance (Å)

CYS435

1.972

LEU438

4.826

Residue

Distance (Å)

CYS439

1.995

THR442

3.818

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Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Ovostatin homolog 1 (OVOS1)	PF00207 ; PF07703 ; PF07677 ; PF17791 ; PF17789 ; PF07678 More >>	70.588 (24/34)	1.29E-05
Polycystic kidney disease 2-like 1 (TRPP2)	PF18109 ; PF08016 ; PF20519 More >>	21.990 (42/191)	1.00E-03
Polycystin-2 (PKD2)	PF18109 ; PF08016 ; PF20519 More >>	24.490 (36/147)	2.00E-03


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
MAPK signaling pathway	hsa04010	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Calcium signaling pathway	hsa04020	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
cGMP-PKG signaling pathway	hsa04022	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
cAMP signaling pathway	hsa04024	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Cardiac muscle contraction	hsa04260	Affiliated Target
Class: Organismal Systems => Circulatory system	Pathway Hierarchy
Adrenergic signaling in cardiomyocytes	hsa04261	Affiliated Target
Class: Organismal Systems => Circulatory system	Pathway Hierarchy
Vascular smooth muscle contraction	hsa04270	Affiliated Target
Class: Organismal Systems => Circulatory system	Pathway Hierarchy
Circadian entrainment	hsa04713	Affiliated Target
Class: Organismal Systems => Environmental adaptation	Pathway Hierarchy
Long-term potentiation	hsa04720	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Retrograde endocannabinoid signaling	hsa04723	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Glutamatergic synapse	hsa04724	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Cholinergic synapse	hsa04725	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Serotonergic synapse	hsa04726	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
GABAergic synapse	hsa04727	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Dopaminergic synapse	hsa04728	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Taste transduction	hsa04742	Affiliated Target
Class: Organismal Systems => Sensory system	Pathway Hierarchy
Insulin secretion	hsa04911	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
GnRH signaling pathway	hsa04912	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Oxytocin signaling pathway	hsa04921	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Renin secretion	hsa04924	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Aldosterone synthesis and secretion	hsa04925	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Cortisol synthesis and secretion	hsa04927	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
GnRH secretion	hsa04929	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Growth hormone synthesis, secretion and action	hsa04935	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	15	Degree centrality	1.61E-03	Betweenness centrality	2.53E-03
Closeness centrality	2.03E-01	Radiality	1.35E+01	Clustering coefficient	2.00E-01
Neighborhood connectivity	1.27E+01	Topological coefficient	1.05E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 24 KEGG Pathways	+
1	MAPK signaling pathway
2	Calcium signaling pathway
3	cGMP-PKG signaling pathway
4	cAMP signaling pathway
5	Cardiac muscle contraction
6	Adrenergic signaling in cardiomyocytes
7	Vascular smooth muscle contraction
8	Circadian entrainment
9	Long-term potentiation
10	Retrograde endocannabinoid signaling
11	Glutamatergic synapse
12	Cholinergic synapse
13	Serotonergic synapse
14	GABAergic synapse
15	Dopaminergic synapse
16	Insulin secretion
17	GnRH signaling pathway
18	Oxytocin signaling pathway
19	Type II diabetes mellitus
20	Alzheimer's disease
21	Amphetamine addiction
22	Hypertrophic cardiomyopathy (HCM)
23	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
24	Dilated cardiomyopathy
NetPath Pathway	[+] 1 NetPath Pathways	+
1	IL2 Signaling Pathway
Panther Pathway	[+] 7 Panther Pathways	+
1	Alzheimer disease-amyloid secretase pathway
2	Nicotinic acetylcholine receptor signaling pathway
3	5HT2 type receptor mediated signaling pathway
4	Beta1 adrenergic receptor signaling pathway
5	Beta2 adrenergic receptor signaling pathway
6	Oxytocin receptor mediated signaling pathway
7	Nicotine pharmacodynamics pathway
Pathwhiz Pathway	[+] 1 Pathwhiz Pathways	+
1	Muscle/Heart Contraction
Reactome	[+] 3 Reactome Pathways	+
1	Adrenaline,noradrenaline inhibits insulin secretion
2	NCAM1 interactions
3	Regulation of insulin secretion
WikiPathways	[+] 6 WikiPathways	+
1	Calcium Regulation in the Cardiac Cell
2	Arrhythmogenic Right Ventricular Cardiomyopathy
3	Alzheimers Disease
4	NCAM signaling for neurite out-growth
5	Integration of energy metabolism
6	Nicotine Activity on Chromaffin Cells

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications. J Med Chem. 1995 Sep 15;38(19):3681-716.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031727)

REF 3

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000253)

REF 4

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 498).

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006771)

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)

REF 7

Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity. J Med Chem. 1989 Oct;32(10):2399-406.

REF 8

CGS 27830, a potent nonpeptide endothelin receptor antagonist, Bioorg. Med. Chem. Lett. 3(10):2099-2104 (1993).

REF 9

Novel calcium antagonists with both calcium overload inhibition and antioxidant activity. 1. 2-(3, 5-di-tert-butyl-4-hydroxyphenyl)-3-(aminopropyl)... J Med Chem. 1998 Oct 22;41(22):4309-16.

REF 10

Design and synthesis of novel dihydropyridine alpha-1a antagonists. Bioorg Med Chem Lett. 1999 Oct 4;9(19):2843-8.

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)

REF 12

Identification of R(-)-isomer of efonidipine as a selective blocker of T-type Ca2+ channels. Br J Pharmacol. 2004 Dec;143(8):1050-7.

REF 13

REF 14

The calcium channel ligand FPL 64176 enhances L-type but inhibits N-type neuronal calcium currents. Neuropharmacology. 2003 Aug;45(2):281-92.

REF 15

Antagonism of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates toward voltage-dependent L-type Ca2+ channels Ca V 1.3 and Ca V 1.2. Bioorg Med Chem. 2010 May 1;18(9):3147-58.

REF 16

Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52.

REF 17

SR 33557, a novel calcium entry blocker. II. Interactions with 1,4-dihydropyridine, phenylalkylamine and benzothiazepine binding sites in rat heart sarcolemmal membranes. J Pharmacol Exp Ther. 1990 Nov;255(2):600-7.

REF 18

Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca 2+ channels. J Clin Invest. 2004 May;113(10):1430-9.

REF 19

Pharmacological, radioligand binding, and electrophysiological characteristics of FPL 64176, a novel nondihydropyridine Ca2+ channel activator, in cardiac and vascular preparations. Mol Pharmacol. 1991 Nov;40(5):734-41.

REF 20

Stapled Voltage-Gated Calcium Channel (Ca(V)) Alpha-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of Ca(V) Function. ACS Chem Neurosci. 2017 Jun 21;8(6):1313-1326.

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