PDBsum entry 7nxk

Transcription

PDB id: 7nxk

Contents

Protein chains

322 a.a.

246 a.a.

Ligands

UUB ×2

Waters ×58

PDB id:

7nxk

Name:

Transcription

Title:

Crystal structure of human cdk12/cyclin k in complex with the inhibitor bsj-01-175

Structure:

Cyclin-dependent kinase 12. Chain: a, c. Synonym: cdc2-related kinase,arginine/serine-rich,crkrs,cell division cycle 2-related protein kinase 7,cdc2-related protein kinase 7,cell division protein kinase 12,hcdk12. Engineered: yes. Cyclin-k. Chain: b, d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk12, crk7, crkrs, kiaa0904. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: ccnk, cpr4. Expression_system_taxid: 7108

Resolution:

3.00Å R-factor: 0.222 R-free: 0.264

Authors:

K.Anand,S.Dust,I.H.Kaltheuner,M.Geyer

Key ref:

B.Jiang et al. (2021). Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma. Eur J Med Chem, 221, 113481. PubMed id: 33945934 DOI: 10.1016/j.ejmech.2021.113481

Date:

18-Mar-21 Release date: 12-May-21

Protein chains

Q9NYV4  (CDK12_HUMAN) -  Cyclin-dependent kinase 12 from Homo sapiens

Seq: 1490 a.a.

Struc: 322 a.a.*

Protein chains

O75909  (CCNK_HUMAN) -  Cyclin-K from Homo sapiens

Seq: 580 a.a.

Struc: 246 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: Chains A, C: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 3: Chains A, C: E.C.2.7.11.23 - [RNA-polymerase]-subunit kinase.
• Reaction: [DNA-directed RNA polymerase] + ATP = phospho-[DNA-directed RNA polymerase] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.ejmech.2021.113481

Eur J Med Chem 221:113481 (2021)

PubMed id: 33945934

Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma.

B.Jiang, J.Jiang, I.H.Kaltheuner, A.B.Iniguez, K.Anand, F.M.Ferguson, S.B.Ficarro, B.K.A.Seong, A.K.Greifenberg, S.Dust, N.P.Kwiatkowski, J.A.Marto, K.Stegmaier, T.Zhang, M.Geyer, N.S.Gray.

ABSTRACT

Development of inhibitors targeting CDK12/13 is of increasing interest as a potential therapy for cancers as these compounds inhibit transcription of DNA damage response (DDR) genes. We previously described THZ531, a covalent inhibitor with selectivity for CDK12/13. In order to elucidate structure-activity relationship (SAR), we have undertaken a medicinal chemistry campaign and established a focused library of THZ531 analogs. Among these analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in cancer cells. A 3.0 Å co-crystal structure with CDK12/CycK provides a structural rational for selective targeting of Cys1039 located in a C-terminal extension from the kinase domain. With moderate pharmacokinetic properties, BSJ-01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day, intraperitoneal administration. Taken together, BSJ-01-175 represents the first selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date.