Target Information

Target General Information

Target ID

T54644 (Former ID: TTDS00413)

Target Name

Voltage-gated calcium channel alpha Cav3.2 (CACNA1H)

Synonyms

Voltage-gated calcium channel subunit alpha Cav3.2; Voltage-dependent T-type calcium channel subunit alpha-1H; Low-voltage-activated calcium channel alpha1 3.2 subunit

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Gene Name

CACNA1H

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Acidosis [ICD-11: 5C73]

Migraine [ICD-11: 8A80]

Function

Voltage-sensitive calcium channel that gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group. A particularity of this type of channel is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle (Probable). They may also be involved in the modulation of firing patterns of neurons. In the adrenal zona glomerulosa, participates in the signaling pathway leading to aldosterone production in response to either AGT/angiotensin II, or hyperkalemia.

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BioChemical Class

Voltage-gated ion channel

UniProt ID

CAC1H_HUMAN

Sequence

MTEGARAADEVRVPLGAPPPGPAALVGASPESPGAPGREAERGSELGVSPSESPAAERGA
ELGADEEQRVPYPALAATVFFCLGQTTRPRSWCLRLVCNPWFEHVSMLVIMLNCVTLGMF
RPCEDVECGSERCNILEAFDAFIFAFFAVEMVIKMVALGLFGQKCYLGDTWNRLDFFIVV
AGMMEYSLDGHNVSLSAIRTVRVLRPLRAINRVPSMRILVTLLLDTLPMLGNVLLLCFFV
FFIFGIVGVQLWAGLLRNRCFLDSAFVRNNNLTFLRPYYQTEEGEENPFICSSRRDNGMQ
KCSHIPGRRELRMPCTLGWEAYTQPQAEGVGAARNACINWNQYYNVCRSGDSNPHNGAIN
FDNIGYAWIAIFQVITLEGWVDIMYYVMDAHSFYNFIYFILLIIVGSFFMINLCLVVIAT
QFSETKQRESQLMREQRARHLSNDSTLASFSEPGSCYEELLKYVGHIFRKVKRRSLRLYA
RWQSRWRKKVDPSAVQGQGPGHRQRRAGRHTASVHHLVYHHHHHHHHHYHFSHGSPRRPG
PEPGACDTRLVRAGAPPSPPSPGRGPPDAESVHSIYHADCHIEGPQERARVAHAAATAAA
SLRLATGLGTMNYPTILPSGVGSGKGSTSPGPKGKWAGGPPGTGGHGPLSLNSPDPYEKI
PHVVGEHGLGQAPGHLSGLSVPCPLPSPPAGTLTCELKSCPYCTRALEDPEGELSGSESG
DSDGRGVYEFTQDVRHGDRWDPTRPPRATDTPGPGPGSPQRRAQQRAAPGEPGWMGRLWV
TFSGKLRRIVDSKYFSRGIMMAILVNTLSMGVEYHEQPEELTNALEISNIVFTSMFALEM
LLKLLACGPLGYIRNPYNIFDGIIVVISVWEIVGQADGGLSVLRTFRLLRVLKLVRFLPA
LRRQLVVLVKTMDNVATFCTLLMLFIFIFSILGMHLFGCKFSLKTDTGDTVPDRKNFDSL
LWAIVTVFQILTQEDWNVVLYNGMASTSSWAALYFVALMTFGNYVLFNLLVAILVEGFQA
EGDANRSDTDEDKTSVHFEEDFHKLRELQTTELKMCSLAVTPNGHLEGRGSLSPPLIMCT
AATPMPTPKSSPFLDAAPSLPDSRRGSSSSGDPPLGDQKPPASLRSSPCAPWGPSGAWSS
RRSSWSSLGRAPSLKRRGQCGERESLLSGEGKGSTDDEAEDGRAAPGPRATPLRRAESLD
PRPLRPAALPPTKCRDRDGQVVALPSDFFLRIDSHREDAAELDDDSEDSCCLRLHKVLEP
YKPQWCRSREAWALYLFSPQNRFRVSCQKVITHKMFDHVVLVFIFLNCVTIALERPDIDP
GSTERVFLSVSNYIFTAIFVAEMMVKVVALGLLSGEHAYLQSSWNLLDGLLVLVSLVDIV
VAMASAGGAKILGVLRVLRLLRTLRPLRVISRAPGLKLVVETLISSLRPIGNIVLICCAF
FIIFGILGVQLFKGKFYYCEGPDTRNISTKAQCRAAHYRWVRRKYNFDNLGQALMSLFVL
SSKDGWVNIMYDGLDAVGVDQQPVQNHNPWMLLYFISFLLIVSFFVLNMFVGVVVENFHK
CRQHQEAEEARRREEKRLRRLERRRRSTFPSPEAQRRPYYADYSPTRRSIHSLCTSHYLD
LFITFIICVNVITMSMEHYNQPKSLDEALKYCNYVFTIVFVFEAALKLVAFGFRRFFKDR
WNQLDLAIVLLSLMGITLEEIEMSAALPINPTIIRIMRVLRIARVLKLLKMATGMRALLD
TVVQALPQVGNLGLLFMLLFFIYAALGVELFGRLECSEDNPCEGLSRHATFSNFGMAFLT
LFRVSTGDNWNGIMKDTLRECSREDKHCLSYLPALSPVYFVTFVLVAQFVLVNVVVAVLM
KHLEESNKEAREDAELDAEIELEMAQGPGSARRVDADRPPLPQESPGARDAPNLVARKVS
VSRMLSLPNDSYMFRPVVPASAPHPRPLQEVEMETYGAGTPLGSVASVHSPPAESCASLQ
IPLAVSSPARSGEPLHALSPRGTARSPSLSRLLCRQEAVHTDSLEGKIDSPRDTLDPAEP
GEKTPVRPVTQGGSLQSPPRSPRPASVRTRKHTFGQRCVSSRPAAPGGEEAEASDPADEE
VSHITSSACPWQPTAEPHGPEASPVAGGERDLRRLYSVDAQGFLDKPGRADEQWRPSAEL
GSGEPGEAKAWGPEAEPALGARRKKKMSPPCISVEPPAEDEGSARPSAAEGGSTTLRRRT
PSCEATPHRDSLEPTEGSGAGGDPAAKGERWGQASCRAEHLTVPSFAFEPLDLGVPSGDP
FLDGSHSVTPESRASSSGAIVPLEPPESEPPMPVGDPPEKRRGLYLTVPQCPLEKPGSPS
ATPAPGGGADDPV

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Flunarizine

Drug Info

Approved

Migraine

[2]

Sodium bicarbonate

Drug Info

Approved

Metabolic acidosis

[3], [4], [5]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

ABT-639

Drug Info

Phase 2

Pain

[6], [7]

Mibefradil

Drug Info

Phase 1

Glioblastoma multiforme

[8]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

TTA-A8

Drug Info

Preclinical

Insomnia

[9], [10]

Mode of Action

[+] 5 Modes of Action

Blocker

[+] 4 Blocker drugs

Flunarizine

Drug Info

[11], [12]

Sodium bicarbonate

Drug Info

[1]

DP-3005

Drug Info

[17]

HYP-10

Drug Info

[17]

Modulator

[+] 2 Modulator drugs

ABT-639

Drug Info

[7]

Z 944

Drug Info

[22]

Inhibitor

[+] 13 Inhibitor drugs

Mibefradil

Drug Info

[13]

U-92032

Drug Info

[15]

Cis-N,5-dibenzyl-6-oxomorpholine-3-carboxamide

Drug Info

[16]

GNF-PF-1967

Drug Info

[18]

GNF-PF-4599

Drug Info

[18]

KYS-05001

Drug Info

[19]

KYS-05040

Drug Info

[19]

KYS-05041

Drug Info

[19]

KYS-05042

Drug Info

[19]

KYS-05050

Drug Info

[20]

KYS-05077

Drug Info

[20]

KYS-05080

Drug Info

[20]

TTL-1177

Drug Info

[17]

Antagonist

[+] 2 Antagonist drugs

TTA-A8

Drug Info

[14]

KST-5468

Drug Info

[17]

Blocker (channel blocker)

[+] 1 Blocker (channel blocker) drugs

ML218

Drug Info

[21]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

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 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). Human Similarity Proteins Human Pathway Affiliation

Different Human System Profiles of Target

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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 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).

Human Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Polycystic kidney disease 2-like 1 (TRPP2)	PF18109 ; PF08016 ; PF20519 More >>	24.590 (45/183)	5.68E-06

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
Circadian entrainment	hsa04713	Affiliated Target
Class: Organismal Systems => Environmental adaptation	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
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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 Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

MAPK signaling pathway

Calcium signaling pathway

Circadian entrainment

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Muscle/Heart Contraction

Reactome

[+] 1 Reactome Pathways

NCAM1 interactions

WikiPathways

[+] 2 WikiPathways

Corticotropin-releasing hormone

NCAM signaling for neurite out-growth

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Acute renal failure. Clin Evid (Online). 2008 Sep 3;2008. pii: 2001.

REF 2

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 012102.

REF 3

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: 4507).

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018509.

REF 6

REF 7

Effects of a T-type calcium channel blocker, ABT-639, on spontaneous activity in C-nociceptors in patients with painful diabetic neuropathy: a randomized controlled trial. Pain. 2015 Nov;156(11):2175-83.

REF 8

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 9

REF 10

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010094)

REF 11

Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. Cell Biochem Biophys. 2009;55(2):81-93.

REF 12

Migraine prophylaxis with calcium antagonists: a haemodynamic study using transcranial Doppler ultrasound. Rev Neurol. 2004 Feb 16-29;38(4):316-9.

REF 13

Mibefradil block of cloned T-type calcium channels. J Pharmacol Exp Ther. 2000 Oct;295(1):302-8.

REF 14

Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents. ACS Med Chem Lett. 2010 Aug 24;1(9):504-9.

REF 15

Discovery of (2S)-1-(4-amino-2,3,5- trimethylphenoxy)-3-[4-[4-(4- fluorobenzyl)phenyl]-1-piperazinyl]-2-propanol dimethanesulfonate (SUN N8075): a ... J Med Chem. 2000 Sep 7;43(18):3372-6.

REF 16

Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5244-8.

REF 17

REF 18

3D pharmacophore based virtual screening of T-type calcium channel blockers. Bioorg Med Chem. 2007 Jan 15;15(2):1091-105.

REF 19

3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett. 2004 Jul 5;14(13):3379-84.

REF 20

Synthesis and biological evaluation of novel T-type calcium channel blockers. Bioorg Med Chem Lett. 2007 Jan 15;17(2):471-5.

REF 21

The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson's Disease. ACS Chem Neurosci. 2011 Dec 21;2(12):730-742.

REF 22

Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model.PLoS One.2015 Aug 14;10(8):e0130012.

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