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This probe is available from Sigma, Cayman Chemical and Tocris.
The negative control (SGC3027N) is available for purchase from Sigma and Tocris.
Probe | Negative control | |
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SGC3027 (Pro-drug of SGC8158) |
| SGC3027N (Pro-drug of SGC8158N) |
Active component | Negative control | |
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SGC8158 | SGC8158N |
A collaboration between SGC, Takeda, and OICR has resulted in the discovery of SGC3027, the first potent, selective and cell active chemical probe for PRMT7. SGC3027 is a pro-drug of SGC8158 which releases the active component upon reduction in the cell by reductases. The in vitro activity of SGC8158, the active component, includes inhibition of PRMT7 with IC50 < 2.5 nM for methylation of H2B (23-37) and greater than 40-fold selectivity over other histone methyltransferases and non-epigenetic targets. In cellular assays using C2C12 cells, SGC3027 inhibits the methylation of HSP70 with IC50 = 2.4 microM.
A closely related compound, SGC3027N, is significantly less active in the cellular assay, and is an ideal control compound for cellular studies.
Data relating to the discovery of this probe is being prepared for publication. In the meantime, in order to facilitate research by the community we are making this compound available through this website
Probe | Negative control | |
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SGC3027 |
| SGC3027N |
Physical and chemical properties for SGC3027 | |
Molecular weight | 786.3 |
Molecular formula | C41H47ClN6O6S |
IUPAC name | 2-(3-((4-((5-(5-amino-2,4,7,9-tetraaza-bicyclo[4.3.0]nona-1(6),2,4,7-tetraen-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl)-methylsulfanyl)-butyl)-((3-(4-chloro-phenyl)-phenyl)-methyl)-amino)-1,1-dimethyl-3-oxo-propyl)-3,5,6-trimethyl-cyclohexa-2,5-diene-1,4-dione |
MollogP | 5.689 |
PSA | 134.2 |
No. of chiral centres | 4 |
No. of rotatable bonds | 15 |
No. of hydrogen bond acceptors | 13 |
No. of hydrogen bond donors | 4 |
Physical and chemical properties for SGC3027N (Negative Control) | |
Molecular weight | 826.3 |
Molecular formula | C44H51ClN6O6S |
IUPAC name | 2-(3-((4-((8-(5-amino-2,4,7,9-tetraaza-bicyclo[4.3.0]nona-1(6),2,4,7-tetraen-9-yl)-3,3-dimethyl-2,4,7-trioxa-bicyclo[3.3.0]octan-6-yl)-methylsulfanyl)-butyl)-((3-(4-chloro-phenyl)-phenyl)-methyl)-amino)-1,1-dimethyl-3-oxo-propyl)-3,5,6-trimethyl-cyclohexa-2,5-diene-1,4-dione |
MollogP | 7.431 |
PSA | 118.9 |
No. of chiral centres | 4 |
No. of rotatable bonds | 15 |
No. of hydrogen bond acceptors | 13 |
No. of hydrogen bond donors | 2 |
SMILES:
SGC3027: CC1=C(C(C(C(C)(CC(N(CC2=CC=CC(C3=CC=C(Cl)C=C3)=C2)CCCCSC[C@@H]4[C@@H](O)[C@@H](O)[C@@H](O4)N5C=NC6=C5N=CN=C6N)=O)C)=C(C1=O)C)=O)C
SGC3027N: CC1=C(C(C(C(C)(CC(N(CC2=CC=CC(C3=CC=C(Cl)C=C3)=C2)CCCCSC[C@@H]4[C@@H]5[C@@H](OC(C)(O5)C)[C@@H](O4)N6C=NC7=C6N=CN=C7N)=O)C)=C(C1=O)C)=O)C
InChI:
SGC3027: InChI=1S/C41H47ClN6O6S/c1-23-24(2)35(51)32(25(3)34(23)50)41(4,5)18-31(49)47(19-26-9-8-10-28(17-26)27-11-13-29(42)14-12-27)15-6-7-16-55-20-30-36(52)37(53)40(54-30)48-22-46-33-38(43)44-21-45-39(33)48/h8-14,17,21-22,30,36-37,40,52-53H,6-7,15-16,18-20H2,1-5H3,(H2,43,44,45)/t30-,36-,37-,40-/m1/s1
SGC3027N: InChI=1S/C44H51ClN6O6S/c1-25-26(2)37(54)34(27(3)36(25)53)43(4,5)20-33(52)50(21-28-11-10-12-30(19-28)29-13-15-31(45)16-14-29)17-8-9-18-58-22-32-38-39(57-44(6,7)56-38)42(55-32)51-24-49-35-40(46)47-23-48-41(35)51/h10-16,19,23-24,32,38-39,42H,8-9,17-18,20-22H2,1-7H3,(H2,46,47,48)/t32-,38-,39-,42-/m1/s1
InChIKey:
SGC3027: MLJVGAYSVYMPSB-MSUKGTQXSA-N
SGC3027N: FJBPSCVGHZASPG-LJVHFRCJSA-N
Two of the largest pharmaceutical companies in Brazil, Aché Laboratories and Eurofarma Laboratories, have partnered with the Brazilian Agency for Industrial Research and Innovation (Embrapii) to fund a medicinal chemistry project at the SGC lab at UNICAMP, Campinas, SP, Brazil.
Aché and Eurofarma will each provide R$2.4M funding over six years with R$3.6M from Embrapii to form the Embrapii “Centro de Química Medicinal de Inovação Aberta” (CQMED, English: “Centre for Open Innovation Medicinal Chemistry”).
This probe is available from Tocris, Cayman Chemical and Sigma.
Its negative control (SGC-AAK1-1N) is available for purchase from Tocris and Sigma.
Probe | Negative control | |
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SGC-AAK1-1 |
| SGC-AAK1-1N |
AAK1 (adaptor protein 2-associated kinase) and BMP2K/BIKE (BMP-2 inducible kinase) comprise half of the numb-associated kinase (NAK) family, which also includes cyclin G associated kinase (GAK) and STK16/MPSK1 (serine/threonine kinase 16/myristoylated and palmitoylated serine/threonine kinase 1).1
AAK1 is a 104 kDa serine/threonine kinase with broad tissue expression. Within the cell AAK1 localizes to the cell membrane and cytoplasm.2 AAK1 is involved in clathrin-mediated endocytosis (CME), both by direct binding to clathrin and by phosphorylation of the medium subunit of AP-2 (adaptor protein 2).3-5 In this manner, AAK1 has been identified as a negative regulator of Wnt signaling via mediation of LRP6 internalization. Studies have implicated multiple roles for AAK1 in influencing Notch signaling, including priming and redistribution of Numb as well as Notch activation.6-7
Relatively less is known about the highly understudied kinase BIKE. BIKE is broadly expressed, and in the cell, it localizes to nuclear speckles.2 BIKE was originally identified as its expression was observed to increase upon bone morphogenic protein (BMP-2)-induced differentiation of a prechondroblastic cell line.8 The same study provided evidence for BIKE having an important regulatory role in attenuating the program of osteoblast differentiation. Proteomic studies identified BIKE as a clathrin vesicle-associated protein and have also identified interaction between BIKE and Numb.9-10
NAK family domain structures
Location of AAK1 and BIKE on kinome tree
Snapshot of crystal structure of acylaminoindazole bound to BIKE
SGC-AAK1-1 is a chemical probe for AAK1 and BIKE that potently targets the ATP-binding site (AAK1 Ki = 9.1 nM; BIKE Ki = 17 nM). Regarding kinase selectivity, only three kinases were observed to bind SGC-AAK1-1 within 30-fold of the KD of AAK1 in a KINOMEscan assay (DiscoverX) at 1 μM followed by KD determinations: RIOK1 (KD = 72 nM), RIOK3 (KD = 290 nM), and PIP5K1C (KD = 260 nM). In a live cell NanoBRET assay (Promega) SGC-AAK1-1 has potency for ectopically expressed full-length AAK1- and BIKE-Nluc fusion proteins (AAK1 IC50 = 230 nM; BIKE IC50 = 1.5 μM).
A chemically related negative control compound, SGC-AAK1-1N, is provided.
Probe | Negative control | |
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SGC-AAK1-1 |
| SGC-AAK1-1N |
Physical and chemical properties for BAY-876 | |
Molecular weight | 427.52 |
Molecular formula | C21H25N5O3S |
IUPAC name | N-(6-(3-((N,N-diethylsulfamoyl)amino)phenyl)-1H-indazol-3-yl)cyclopropanecarboxamide |
MollogP | 4.185 |
PSA | 89.47 |
No. of chiral centres | 0 |
No. of rotatable bonds | 9 |
No. of hydrogen bond acceptors | 8 |
No. of hydrogen bond donors | 3 |
Storage | -20 °C as DMSO stock |
Dissolution | Soluble in DMSO at least up to 10 mM |
Physical and chemical properties for BAY-588 (Negative Control) | |
Molecular weight | 398.48 |
Molecular formula | C20H22N4O3S |
IUPAC name | N-(6-(3-(cyclopropanesulfonamido)phenyl)-1H-indazol-3-yl)isobutyramide |
MollogP | 3.381 |
PSA | 87.62 |
No. of chiral centres | 0 |
No. of rotatable bonds | 7 |
No. of hydrogen bond acceptors | 7 |
No. of hydrogen bond donors | 3 |
Storage | -20 °C as DMSO stock |
Dissolution | Soluble in DMSO at least up to 10 mM |
SMILES:
SGC-AAK1-1: O=C(NC1=NNC2=C1C=CC(C3=CC(NS(N(CC)CC)(=O)=O)=CC=C3)=C2)C4CC4
SGC-AAK1-1N: O=C(NC1=NNC2=C1C=CC(C3=CC(NS(C4CC4)(=O)=O)=CC=C3)=C2)C(C)C
InChI:
SGC-AAK1-1: InChI=1S/C21H25N5O3S/c1-3-26(4-2)30(28,29)25-17-7-5-6-15(12-17)16-10-11-18-19(13-16)23-24-20(18)22-21(27)14-8-9-14/h5-7,10-14,25H,3-4,8-9H2,1-2H3,(H2,22,23,24,27)
SGC-AAK1-1N: InChI=1S/C20H22N4O3S/c1-12(2)20(25)21-19-17-9-6-14(11-18(17)22-23-19)13-4-3-5-15(10-13)24-28(26,27)16-7-8-16/h3-6,9-12,16,24H,7-8H2,1-2H3,(H2,21,22,23,25)
InChIKey:
SGC-AAK1-1: UCBIQZUJJSVQHL-UHFFFAOYSA-N
SGC-AAK1-1N: RAIAORGFMNXPOV-UHFFFAOYSA-N
This probe is available from Tocris, Cayman Chemical and Sigma.
Its negative control (SGC-GAK-1N) is available for purchase from Sigma.
Probe | Negative control | |
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SGC-GAK-1 |
| SGC-GAK-1N |
Cyclin G associated kinase (GAK) is a 160 kDa serine/threonine kinase originally identified and so named as a direct association partner with cyclin G.1 GAK is a member of the numb-associated kinase (NAK) family, which includes AAK1 (adaptor protein 2-associated kinase), STK16/MPSK1 (serine/threonine kinase 16/myristoylated and palmitoylated serine/threonine kinase 1), and BMP2K/BIKE (BMP-2 inducible kinase).2 In addition to its kinase domain, the C-terminus of GAK protein bears high homology to a domain found in auxilin and tensin.3 GAK has ubiquitous tissue expression and within the cell localizes to the Golgi complex, cytoplasm, and nucleus.
NAK family domain structures
Location of GAK on kinome tree
Multiple biological roles for GAK and disease associations have been made despite it being a relatively understudied kinase. GAK is involved in membrane trafficking and sorting of proteins, including as an essential cofactor for HSC70-dependent uncoating of clathrin coated vesicles in the cytoplasm.6-7 GAK is required for maintenance of centrosome maturation and progression through mitosis.8 GAK is over-expressed in osteosarcoma cell lines and tissues where it contributes to proliferation and survival.9 Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms in the GAK gene associated with susceptibility to Parkinson’s disease.10 Emerging evidence suggests that GAK may be a therapeutic target in prostate cancer (PCa): GAK expression levels increase upon prolonged androgen treatment and during the progression of cells to hormone independence, and analysis of patient-derived tissue samples demonstrated that GAK expression levels positively correlated with the Gleason score, a quantitative scale of PCa aggressiveness.11 GAK interacts directly with the androgen receptor (AR) and potentiates its transcriptional activity.12 Further elucidation of the role of GAK in these and other biological processes would be facilitated by access to a potent and selective inhibitor of the kinase.
SGC-GAK-1 is a chemical probe for GAK that potently targets the ATP-binding site (KD = 1.9 nM). Regarding kinase selectivity, no kinases were observed to bind SGC-GAK-1 within 30-fold of the KD of GAK in a KINOMEscan assay (DiscoverX) at 1 μM followed by KD determinations. In a live cell NanoBRET assay (Promega) SGC-GAK-1 had an IC50 of 110 nM against ectopically expressed full-length GAK-Nluc fusion.
A chemically related negative control compound, SGC-GAK-1N, is provided.
Despite weakly binding RIPK2 in weakly binding RIPK2 in vitro (DiscoverX RIPK2 KD = 110 nM; 58-fold of GAK KD), SGC-GAK-1 potently engaged RIPK2 in a live cell NanoBRET assay (RIPK2 IC50 = 360 nM); accordingly, we have identified a control compound that is a highly cell-potent RIPK2 ligand, HY-19764, (IC50 = 2.2 nM) that lacks GAK affinity (IC50 > 10 µM).
Probe | Negative control | |
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SGC-GAK-1 |
| SGC-GAK-1N |
Physical and chemical properties for BAY-876 | |
Molecular weight | 389.25 |
Molecular formula | C38H36BrF3N4O6 |
IUPAC name | 6-Bromo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine |
MollogP | 4.65 |
PSA | 40.19 |
No. of chiral centres | 0 |
No. of rotatable bonds | 5 |
No. of hydrogen bond acceptors | 4 |
No. of hydrogen bond donors | 1 |
Storage | -20 °C as DMSO stock |
Dissolution | Soluble in DMSO at least up to 10 mM |
Physical and chemical properties for BAY-588 (Negative Control) | |
Molecular weight | 392.38 |
Molecular formula | C20H19F3N2O3 |
IUPAC name | N-methyl-6-(trifluoromethyl)-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine |
MollogP | 5.157 |
PSA | 33.85 |
No. of chiral centres | 0 |
No. of rotatable bonds | 6 |
No. of hydrogen bond acceptors | 4 |
No. of hydrogen bond donors | 0 |
Storage | -20 °C as DMSO stock |
Dissolution | Soluble in DMSO at least up to 10 mM |
SMILES:
SGC-GAK1-1: BrC1=CC2=C(N=CC=C2NC3=CC(OC)=C(C(OC)=C3)OC)C=C1
SGC-GAK1-1N: CN(C1=C2C(C=CC(C(F)(F)F)=C2)=NC=C1)C3=CC(OC)=C(C(OC)=C3)OC
InChI:
SGC-GAK1-1: InChI=1S/C18H17BrN2O3/c1-22-16-9-12(10-17(23-2)18(16)24-3)21-15-6-7-20-14-5-4-11(19)8-13(14)15/h4-10H,1-3H3,(H,20,21)
SGC-GAK1-1N: InChI=1S/C20H19F3N2O3/c1-25(13-10-17(26-2)19(28-4)18(11-13)27-3)16-7-8-24-15-6-5-12(9-14(15)16)20(21,22)23/h5-11H,1-4H3
InChIKey:
SGC-GAK1-1: AUOSKLDNVNGKRR-UHFFFAOYSA-N
SGC-GAK1-1N: PVTQCCFMFWASHK-UHFFFAOYSA-N
Kiev, Ukraine and Oxford, UK, 10 January 2018: Diamond Light Source (Diamond) and the Structural Genomic Consortium (SGC) Oxford announced today that Enamine, a chemical company and producer of novel chemical building blocks and screening libraries, will become a key supplier of poised fragment and analogue libraries to its XChem facility. Enamine will offer a new generation of the hit-finding library, Diamond-SGC-iNEXT (DSI) Poised Library to enable fast and productive fragment-based lead discovery(FBLD).
This probe is available from Tocris, Cayman Chemical, Sigma and opnMe.com.
Probe | Negative control | |
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BI01383298 |
| BI01372674 |
SLC13A5 (NaCT, INDY) is a sodium-citrate co-transporter that is highly expressed in the liver. It is a member of the SLC13 family of which there are 4 other members. SLC13A5 transports citrate from the circulatory system into hepatocytes where it is used in the synthesis of sterols and fatty acids. SLC13A5 was first identified in Drosophila where the name I’m Not Dead Yet or INDY was coined. A study in 2000(1) showed that lower expression of SLC13A5 in Drosophila led to increased lifespan. Mouse models have demonstrated the potential of this protein as a target for obesity and diabetes with knockout mice protected from adiposity (2), reduced lipid concentrations in a siRNA study (3) and a substrate analogue used to lower blood glucose levels (4). More recently mutations in SLC13A5 have been linked to early-infantile epileptic encephalopathy (5) while silencing of the SLC13A5 gene inhibits proliferation of human hepatocarcinoma cells (6).
BI1383298 is a potent inhibitor of SLC13A5 which unlike previously published inhibitors (4,7) has no structural homology to the substrate (citrate). It is selective over other family members and other transporters. A chemically related negative control (BI01372674) is also provided.
In addition to the chemical probe (BI01383298) we also include a negative control (BI01372674) which is chemically analogous to the probe molecule.
The probe molecule (BI01383298) and control (BI01372674) are soluble, after visual inspection, at 10 µM and 200µM in the presence of 0.1% DMSO in media and assay buffer.
Aliquots of stock Solutions were prepared as follows: 10mM BI01383298 in DMSO (Stored -20oC), 5mM BI01383298 in DMSO (Stored -20oC, need agitation upon thaw and gentle warming to 30oC).
BI01383298 but not BI01372674 demonstrates target engagement in vitro with purified human SLC13A5 protein as shown using a thermostabilisation assay with the Prometheus label-free system from Nanotemper (figure 2).
Figure 2: Thermostabilisation of human SLC13A5 by BI01383298 and BI01372674 between 0.1µM and 10µM. SLC13A5 assay concentration of 1µM. Data summarises 3 biological samples with between 4 and 8 replicates for each.
Probe | Negative control | |
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BI01383298 |
| BI01372674 |
Physical and chemical properties for BI01383298 | |
Molecular weight | 444.0 |
Molecular formula | C19H19Cl2FN2O3S |
IUPAC name | (1-(3,5-dichloro-phenylsulfonyl)-piperidin-4-yl)-((4-fluoro-phenyl)-methylamino)-methanone |
MollogP | 4.64 |
PSA | 56.3 |
No. of chiral centres | 0 |
No. of rotatable bonds | 6 |
No. of hydrogen bond acceptors | 7 |
No. of hydrogen bond donors | 1 |
Physical and chemical properties for BI1372674 (Negative Control) | |
Molecular weight | 502.1 |
Molecular formula | C21H25Cl2N2O4PS |
IUPAC name | |
MollogP | 3.54 |
PSA | 69.5 |
No. of chiral centres | 0 |
No. of rotatable bonds | 7 |
No. of hydrogen bond acceptors | 9 |
No. of hydrogen bond donors | 1 |
SMILES:
BI01383298: FC(C=C1)=CC=C1CNC(C2CCN(S(C3=CC(Cl)=CC(Cl)=C3)(=O)=O)CC2)=O
BI1372674: ClC1=CC(Cl)=CC(S(=O)(N2CCC(CC2)C(NCC3=CC=C(C=C3)P(C)(C)=O)=O)=O)=C1
InChI:
BI01383298: InChI=1S/C19H19Cl2FN2O3S/c20-15-9-16(21)11-18(10-15)28(26,27)24-7-5-14(6-8-24)19(25)23-12-13-1-3-17(22)4-2-13/h1-4,9-11,14H,5-8,12H2,(H,23,25)
BI1372674: InChI=1S/C21H25Cl2N2O4PS/c1-30(2,27)19-5-3-15(4-6-19)14-24-21(26)16-7-9-25(10-8-16)31(28,29)20-12-17(22)11-18(23)13-20/h3-6,11-13,16H,7-10,14H2,1-2H3,(H,24,26)
InChIKey:
BI01383298: VUOYAALVGSMUHC-UHFFFAOYSA-N
BI1372674: GSNNWZZIEKEEQF-UHFFFAOYSA-N
Solvent | BI01383298 | BI01372674 | |
Solubility (200uM, 4% DMSO) | Assay Buffer*- 0hr | Soluble | Soluble |
Assay Buffer*- 12hrs | Soluble | Soluble | |
Freestyle Media- 0hr | Soluble | Soluble | |
Freestyle Media- 12hr | Soluble | Soluble | |
Water- 0hrs | ppt. observed | ppt. observed | |
Solubility (10uM, 0.1% DMSO) | Assay Buffer*- 0hr | Soluble | Soluble |
Assay Buffer*- 12hrs | Soluble | Soluble | |
Freestyle Media- 0hr | Soluble | Soluble | |
Freestyle Media- 12hr | Soluble | Soluble | |
Water- 0hrs | Soluble | Soluble |
*50mM HEPES (pH 7.5), 200mM NaCl, 0.024% n-Dodecyl-β-D-Maltopyranoside, 0.0024% Cholesterol Hemisuccinate.
BI01383298 is more than 1000-fold selective (table 1) over the closest family members: human SLC13A2 / SLC13A3 that share physiological substrates citrate and succinate.
Table 1: Citrate uptake inhibition was measured for all citrate transporters and glycine uptake measured to GLYT2. Potency was assessed for the probe candidate and the negative control on uptake of 14C-citrate into cells over-expressing SLC13A5, SLC13A2, SLC13A3, mouse SLC13A5 and in HEPG2 cells.
Substrate uptake inhibition IC50 [nM] | ||
BI01383298 | BI01372674 | |
HEK cells- hSLC13A5 | 56 | >100,000 |
HepG2 cells | 24 | >100,000 |
HEK cells- mSLC13A5 | >100,000 | 88,000 |
HEK cells- hSLC13A2 | >100,000 | n.d. |
HEK cells- hSLC13A3 | >100,000 | n.d. |
HEK cells – GLYT2 | >100,000 | >100,000 |
Selectivity panel (% inhibition @ 10μM): 35/38 targets<50%; CB1(h): 78%; K(KOP): 81%; Na+channel: 52%
BI01383298 is a potent inhibitor of SLC13A5 with an apparent IC50 value of 56nM in HEK cells overexpressing SLC13A5 and 24nM in HepG2 cell expressing endogenous SLC13A5. BI01383298 was not found to inhibit citrate transport in HEK cells over-expressing mouse SLC13A5 and thus we do not recommend this compound for use in mouse models. BI01372674 was not found to inhibit citrate uptake in a HEPG2 model expressing endogenous levels of SLC13A5 or in HEK cellular models over-expressing human SLC13A5, mouse SLC13A5 or GLYT2.
Figure 1: Measured IC50 of hSLC13A5-mediated 14C-citrate in (A) overexpressed, HEK293-Flp-In-hSLC13A5 and (B) endogenous, HepG2 celluar models.
Pharmaceutical research and development (R & D) is one of the best examples of human ingenuity, attracting vast funding, employing brilliant minds, and deploying the most advanced technologies. Over the past century, it has enabled unprecedented advances for human health. Yet the pharmaceutical R & D system is struggling to keep up with society’s medical needs.
A new partnership between the Structural Genomics Consortium (SGC) and the Montreal Neurological Institute and Hospital (The Neuro) will use a unique open science framework to help scientists discover new targets for drug development for neurological diseases.