PDBsum entry 6t6d

Signaling protein

PDB id: 6t6d

Contents

Protein chains

292 a.a.

278 a.a.

Ligands

MM8 ×4

SO4 ×11

Waters ×30

PDB id:

6t6d

Name:

Signaling protein

Title:

Crystal structure of the acvr1 (alk2) kinase in complex with the compound m4k2149

Structure:

Activin receptor type i. Chain: a, b, c, d. Engineered: yes. Mutation: yes. Other_details: chains e, f, g and h contain ligand 149 bound to the kinase active site and so4 as part of the crystal packing.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: acvr1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9

Resolution:

2.56Å R-factor: 0.224 R-free: 0.272

Authors:

R.J.Adamson,E.P.Williams,D.Smil,N.Burgess-Brown,F.Von Delft, C.H.Arrowsmith,A.M.Edwards,C.Bountra,A.N.Bullock

Key ref:

D.Ensan et al. (2020). Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma. J Med Chem, 63, 4978-4996. PubMed id: 32369358 DOI: 10.1021/acs.jmedchem.0c00395

Date:

18-Oct-19 Release date: 30-Oct-19

Protein chains

Q04771  (ACVR1_HUMAN) -  Activin receptor type-1 from Homo sapiens

Seq: 509 a.a.

Struc: 292 a.a.*

Protein chains

Q04771  (ACVR1_HUMAN) -  Activin receptor type-1 from Homo sapiens

Seq: 509 a.a.

Struc: 278 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.2.7.11.30 - receptor protein serine/threonine kinase.
• Reaction:
  1. L-seryl-[receptor-protein] + ATP = O-phospho-L-seryl-[receptor- protein] + ADP + H⁺
  2. L-threonyl-[receptor-protein] + ATP = O-phospho-L-threonyl-[receptor- protein] + ADP + H⁺

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

reference

DOI no: 10.1021/acs.jmedchem.0c00395

J Med Chem 63:4978-4996 (2020)

PubMed id: 32369358

Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.

D.Ensan, D.Smil, C.A.Zepeda-Velázquez, D.Panagopoulos, J.F.Wong, E.P.Williams, R.Adamson, A.N.Bullock, T.Kiyota, A.Aman, O.G.Roberts, A.M.Edwards, J.A.O'Meara, M.B.Isaac, R.Al-Awar.

ABSTRACT

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-βR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.