Target Information
| Target General Information | Top | |||||
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| Target ID |
T28484
(Former ID: TTDC00143)
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| Target Name |
Kinesin-like protein KIF11 (KIF11)
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| Synonyms |
Thyroid receptor interacting protein 5; TRIP5; Kinesin-related motor protein Eg5; Kinesin-like spindle protein HKSP; Kinesin-like protein 1; KIF11; Eg5
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| Gene Name |
KIF11
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 8 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Head and neck cancer [ICD-11: 2D42] | |||||
| 3 | Multiple myeloma [ICD-11: 2A83] | |||||
| 4 | Ovarian cancer [ICD-11: 2C73] | |||||
| 5 | Renal cell carcinoma [ICD-11: 2C90] | |||||
| 6 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 7 | Lymphoma [ICD-11: 2A80-2A86] | |||||
| 8 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| Function |
Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.
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| BioChemical Class |
Kinesin-like protein family
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| UniProt ID | ||||||
| Sequence |
MASQPNSSAKKKEEKGKNIQVVVRCRPFNLAERKASAHSIVECDPVRKEVSVRTGGLADK
SSRKTYTFDMVFGASTKQIDVYRSVVCPILDEVIMGYNCTIFAYGQTGTGKTFTMEGERS PNEEYTWEEDPLAGIIPRTLHQIFEKLTDNGTEFSVKVSLLEIYNEELFDLLNPSSDVSE RLQMFDDPRNKRGVIIKGLEEITVHNKDEVYQILEKGAAKRTTAATLMNAYSSRSHSVFS VTIHMKETTIDGEELVKIGKLNLVDLAGSENIGRSGAVDKRAREAGNINQSLLTLGRVIT ALVERTPHVPYRESKLTRILQDSLGGRTRTSIIATISPASLNLEETLSTLEYAHRAKNIL NKPEVNQKLTKKALIKEYTEEIERLKRDLAAAREKNGVYISEENFRVMSGKLTVQEEQIV ELIEKIGAVEEELNRVTELFMDNKNELDQCKSDLQNKTQELETTQKHLQETKLQLVKEEY ITSALESTEEKLHDAASKLLNTVEETTKDVSGLHSKLDRKKAVDQHNAEAQDIFGKNLNS LFNNMEELIKDGSSKQKAMLEVHKTLFGNLLSSSVSALDTITTVALGSLTSIPENVSTHV SQIFNMILKEQSLAAESKTVLQELINVLKTDLLSSLEMILSPTVVSILKINSQLKHIFKT SLTVADKIEDQKKELDGFLSILCNNLHELQENTICSLVESQKQCGNLTEDLKTIKQTHSQ ELCKLMNLWTERFCALEEKCENIQKPLSSVQENIQQKSKDIVNKMTFHSQKFCADSDGFS QELRNFNQEGTKLVEESVKHSDKLNGNLEKISQETEQRCESLNTRTVYFSEQWVSSLNER EQELHNLLEVVSQCCEASSSDITEKSDGRKAAHEKQHNIFLDQMTIDEDKLIAQNLELNE TIKIGLTKLNCFLEQDLKLDIPTGTTPQRKSYLYPSTLVRTEPREHLLDQLKRKQPELLM MLNCSENNKEETIPDVDVEEAVLGQYTEEPLSQEPSVDAGVDCSSIGGVPFFQHKKSHGK DKENRGINTLERSKVEETTEHLVTKSRLPLRAQINL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T20C6X | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | ARRY-520 | Drug Info | Phase 2 | Solid tumour/cancer | [5] | |
| 2 | AZD-4877 | Drug Info | Phase 2 | Acute myeloid leukaemia | [6], [7] | |
| 3 | Ispinesib | Drug Info | Phase 2 | Solid tumour/cancer | [8] | |
| 4 | 4SC-205 | Drug Info | Phase 1 | Lymphoma | [10] | |
| 5 | ARQ 621 | Drug Info | Phase 1 | Haematological malignancy | [11] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | ARRY-520 | Drug Info | [1], [12] | |||
| 2 | AZD-4877 | Drug Info | [13] | |||
| 3 | Ispinesib | Drug Info | [14], [15], [16] | |||
| 4 | 4SC-205 | Drug Info | [10] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | ARQ 621 | Drug Info | [13] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: ARRY-520 | Ligand Info | |||||
| Structure Description | Eg5-inhibitor complex | PDB:6HKY | ||||
| Method | X-ray diffraction | Resolution | 2.75 Å | Mutation | No | [17] |
| PDB Sequence |
GKNIQVVVRC
25 RPFNLAERKA35 SAHSIVECDP45 VRKEVSVRTG55 GLADKSSRKT65 YTFDMVFGAS 75 TKQIDVYRSV85 VCPILDEVIM95 GYNCTIFAYG105 QTGTGKTFTM115 EGERSPNEEY 125 TWEEDPLAGI135 IPRTLHQIFE145 KLTDNGTEFS155 VKVSLLEIYN165 EELFDLLNPS 175 SDVSERLQMF185 DDPRNKRGVI195 IKGLEEITVH205 NKDEVYQILE215 KGAAKRTTAA 225 TLMNAYSSRS235 HSVFSVTIHM245 KEELVKIGKL261 NLVDLAGSEN271 NINQSLLTLG 296 RVITALVERT306 PHVPYRESKL316 TRILQDSLGG326 RTRTSIIATI336 SPASLNLEET 346 LSTLEYAHRA356 KNILNKPE
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THR112
4.208
MET115
4.686
GLU116
3.080
GLY117
2.840
GLU118
2.923
ARG119
3.147
TRP127
4.199
ASP130
4.619
LEU132
4.836
ALA133
3.473
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: EMD-534085 | Ligand Info | |||||
| Structure Description | X-ray structure of mitotic kinesin-5 (KSP, KIF11, Eg5)in complex with the hexahydro-2H-pyrano[3,2-c]quinoline EMD 534085 | PDB:3L9H | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [18] |
| PDB Sequence |
GKNIQVVVRC
25 RPFNLAERKA35 SAHSIVECDP45 VRKEVSVRTG55 GLADKSSRKT65 YTFDMVFGAS 75 TKQIDVYRSV85 VCPILDEVIM95 GYNCTIFAYG105 QTGTGKTFTM115 EGERSPNEEY 125 TWEEDPLAGI135 IPRTLHQIFE145 KLTDNGTEFS155 VKVSLLEIYN165 EELFDLLNPS 175 SDVSERLQMF185 DDPRNKRGVI195 IKGLEEITVH205 NKDEVYQILE215 KGAAKRTTAA 225 TLMNAYSSRS235 HSVFSVTIHM245 KETTIDGEEL255 VKIGKLNLVD265 LAGSENINQS 291 LLTLGRVITA301 LVERTPHVPY311 RESKLTRILQ321 DSLGGRTRTS331 IIATISPASL 341 NLEETLSTLE351 YAHRAKNILN361 K
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GLU116
3.098
GLY117
4.110
GLU118
3.507
ARG119
3.518
PRO121
4.873
TRP127
3.542
ASP130
4.645
LEU132
4.713
ALA133
3.561
GLY134
4.916
ILE136
3.941
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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 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).
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
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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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.
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| Degree | 54 | Degree centrality | 5.80E-03 | Betweenness centrality | 1.02E-03 |
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| Closeness centrality | 2.22E-01 | Radiality | 1.39E+01 | Clustering coefficient | 4.01E-01 |
| Neighborhood connectivity | 3.57E+01 | Topological coefficient | 1.02E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | MHC class II antigen presentation | |||||
| 2 | Kinesins | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | MHC class II antigen presentation | |||||
| 2 | Kinesins | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells. Leukemia. 2009 Oct;23(10):1755-62. | |||||
| REF 2 | ClinicalTrials.gov (NCT00343564) A Study of SB-743921 in Non-Hodgkin's Lymphoma. U.S. National Institutes of Health. | |||||
| REF 3 | A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose. Cancer Chemother Pharmacol. 2011 Feb;67(2):447-54. | |||||
| REF 4 | ClinicalTrials.gov (NCT01416389) A Study of LY2523355 in Patients With Breast Cancer. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT01989325) A Study of Filanesib (ARRY-520) and Carfilzomib in Patients With Advanced Multiple Myeloma. U.S. National Institutes of Health. | |||||
| REF 6 | 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: 7708). | |||||
| REF 7 | ClinicalTrials.gov (NCT00661609) A Phase II Study of AZD4877 (a Novel Anti-mitotic Agent) in Advanced Bladder Cancer. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT00095628) SB-715992 in Treating Patients With Recurrent or Metastatic Head and Neck Cancer. U.S. National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT00104364) A Study of MK0731 in Patients With Advanced Solid Tumors (0731-002)(COMPLETED). U.S. National Institutes of Health. | |||||
| REF 10 | 2011 Pipeline of 4SC AG. | |||||
| REF 11 | ClinicalTrials.gov (NCT00825487) Dose Escalation Study of ARQ 621 in Adult Patients With Metastatic Solid Tumors and Hematologic Malignancies. U.S. National Institutes of Health. | |||||
| REF 12 | Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Nov;29(9):625-55. | |||||
| REF 13 | Kinesins and cancer. Nat Rev Cancer. 2012 Jul 24;12(8):527-39. | |||||
| REF 14 | Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2009 Dec 15;53(7):1255-63. | |||||
| REF 15 | KIF11 inhibition for glioblastoma treatment: reason to hope or a struggle with the brain BMC Cancer. 2009 Jun 22;9:196. | |||||
| REF 16 | Gateways to clinical trials. July-August 2008. Methods Find Exp Clin Pharmacol. 2008 Jul-Aug;30(6):459-95. | |||||
| REF 17 | Is the Fate of Clinical Candidate Arry-520 Already Sealed? Predicting Resistance in Eg5-Inhibitor Complexes. Mol Cancer Ther. 2019 Dec;18(12):2394-2406. | |||||
| REF 18 | The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1491-5. | |||||
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