PDBsum entry 5osk

Cell cycle

PDB id: 5osk

Contents

Protein chains

437 a.a.

421 a.a.

123 a.a.

316 a.a.

Ligands

GTP ×2

GOL ×7

GDP ×2

MES

A9Q

IMD ×2

ACP

Metals

_MG ×5

_CA

Waters ×844

PDB id:

5osk

Name:

Cell cycle

Title:

Tubulin-7j complex

Structure:

Tubulin alpha-1b chain. Chain: a, c. Synonym: alpha-tubulin ubiquitous,tubulin k-alpha-1,tubulin alpha- ubiquitous chain. Tubulin beta-2b chain. Chain: b, d. Stathmin-4. Chain: e. Synonym: stathmin-like protein b3,rb3.

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Tissue: brain. Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: stmn4. Expressed in: escherichia coli.

Resolution:

2.11Å R-factor: 0.197 R-free: 0.232

Authors:

G.Menchon,A.E.Prota,M.O.Steinmetz,B.V.L.Potter

Key ref:

W.Dohle et al. (2018). Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure. J Med Chem, 61, 1031-1044. PubMed id: 29227648 DOI: 10.1021/acs.jmedchem.7b01474

Date:

17-Aug-17 Release date: 20-Dec-17

Protein chains

P81947  (TBA1B_BOVIN) -  Tubulin alpha-1B chain from Bos taurus

Seq: 451 a.a.

Struc: 437 a.a.

Protein chains

Q6B856  (TBB2B_BOVIN) -  Tubulin beta-2B chain from Bos taurus

Seq: 445 a.a.

Struc: 421 a.a.

Protein chain

P63043  (STMN4_RAT) -  Stathmin-4 from Rattus norvegicus

Seq: 189 a.a.

Struc: 123 a.a.

Protein chain

E1BQ43  (E1BQ43_CHICK) -

DOI no: 10.1021/acs.jmedchem.7b01474

J Med Chem 61:1031-1044 (2018)

PubMed id: 29227648

Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure.

W.Dohle, F.L.Jourdan, G.Menchon, A.E.Prota, P.A.Foster, P.Mannion, E.Hamel, M.P.Thomas, P.G.Kasprzyk, E.Ferrandis, M.O.Steinmetz, M.P.Leese, B.V.L.Potter.

ABSTRACT

Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI₅₀300 nM). A preliminary structure-activity relationship afforded compounds (e.g., 7j GI₅₀50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template.