PDBsum entry 4og5

Protein binding/inhibitor

PDB id: 4og5

Contents

Protein chain

469 a.a.

Ligands

2S7

SO4 ×2

PG4

PEG

DMS ×3

TBF

Waters ×373

PDB id:

4og5

Name:

Protein binding/inhibitor

Title:

Human menin with bound inhibitor miv-5

Structure:

Menin. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: men1, scg2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.63Å R-factor: 0.164 R-free: 0.194

Authors:

S.He,T.J.Senter,J.W.Pollock,C.Han,S.K.Upadhyay,T.Purohit, R.D.Gogliotti,C.W.Lindsley,T.Cierpicki,S.R.Stauffer,J.Grembecka

Key ref:

S.He et al. (2014). High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction. J Med Chem, 57, 1543-1556. PubMed id: 24472025 DOI: 10.1021/jm401868d

Date:

15-Jan-14 Release date: 05-Mar-14

Protein chain

O00255  (MEN1_HUMAN) -  Menin from Homo sapiens

Seq: 610 a.a.

Struc: 469 a.a.

DOI no: 10.1021/jm401868d

J Med Chem 57:1543-1556 (2014)

PubMed id: 24472025

High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction.

S.He, T.J.Senter, J.Pollock, C.Han, S.K.Upadhyay, T.Purohit, R.D.Gogliotti, C.W.Lindsley, T.Cierpicki, S.R.Stauffer, J.Grembecka.

ABSTRACT

The protein-protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin-MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of ∼288000 small molecules. We determined menin-inhibitor co-crystal structures and found that these compounds closely mimic all key interactions of MLL with menin. Extensive crystallography studies combined with structure-based design were applied for optimization of these compounds, resulting in MIV-6R, which inhibits the menin-MLL interaction with IC50 = 56 nM. Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia cells, validating specific mechanism of action. Our studies provide novel and attractive scaffold as a new potential therapeutic approach for MLL leukemias and demonstrate an example of PPI amenable to inhibition by small molecules.