A scholarship-funded DPhil (PhD) studentship position is available at the SGC, 
University of Oxford, for the academic year starting October 2017.  The closing 
date for applications will be 12 noon UK time, 6th January 2017. Interviews 
will take place on 24th & 25th January 2017.  Scholarship is available for UK 
nationals only, but funding options are available for other nationalities.  
Application and project details are copied below:

Characterisation of the drug target ACVR1/ALK2

Supervisors: Dr Alex Bullock, Dr Gillian Farnie

Project Overview

A multidisciplinary DPhil project is available using structural, cellular and 
chemical biology approaches to advance our ongoing drug discovery efforts 
targeting the BMP receptor kinase ALK2, encoded by the gene ACVR1. Gain of 
function mutations in the intracellular kinase domain of ALK2/ACVR1 cause the 
childhood brain tumour DIPG (diffuse intrinsic pontine glioma) and the rare 
bone disease FOP (fibrodysplasia ossificans progressiva) (Nat Genet. 2014; 46, 
457-61). There are currently no effective treatments for either condition and 
prognosis is poor.

The ALK2 kinase is a member of the BMP/TGF-beta receptor family that activates 
both the Smad transcription factor and p38 MAPK signaling pathways by 
phosphorylation. Ligands of the BMP/TGF-β superfamily (BMPs, Nodal, Activins, 
GDFs, TGF-βs) are secreted growth factors well known for their roles in 
determining stem cell fate and tissue repair.  While some members such as GDF11 
have been controversially famed as the "elixir of youth" (Science 2014; 344, 
649-52), many are oppositely linked to human disease.

You will elucidate the molecular mechanisms that cause ALK2 deregulation and 
characterize the actions and potency of small molecule ALK2 inhibitors in 
development in our group (J Med Chem 2014; 57, 7900-15).  Key questions 
include: how does ALK2 activity drive cancer? How do the disease mutations 
affect the receptor's structure and function?  How are different signalling 
pathways affected?  What protein-protein interactions are changed? Why do 
oncogenic ALK2/ACVR1 mutations occur together with specific Histone H3 K27M 
mutations? Do epigenetic inhibitors improve the efficacy of ALK2 inhibitors?

Training Opportunities

You will learn about protein structure, cellular signalling and drug discovery. 
Training will be given in all aspects of molecular biology from routine cloning 
and mutagenesis to protein expression and purification using bacterial and 
human cells. Wild-type and mutant proteins will be analysed using 
bioinformatic, cellular, biochemical and biophysical techniques (including mass 
spectrometry, fluorescence plate readers and calorimetry).  As part of the 
Structural Genomics Consortium (SGC) you will make use of state of art 
facilities for protein crystallisation, X-ray diffraction and structure 
determination. The student will also benefit from extensive collaborations with 
international collaborators, patient groups, clinicians and pharmaceutical 
companies. A named scholarship is available for this project for candidates 
with UK nationality and residency.


For informal queries, contact: alex.bull...@sgc.ox.ac.uk


Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, 
Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim 
MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, Wagers AJ. (2014). Restoring 
systemic GDF11 levels reverses age-related dysfunction in mouse skeletal 
muscle. Science, 344, pp. 649-52.

Chaikuad A, Alfano I, Kerr G, Sanvitale CE, Boergermann JH, Triffitt JT, von 
Delft F, Knapp S, Knaus P, Bullock AN. (2012). Structure of the bone 
morphogenetic protein receptor ALK2 and implications for fibrodysplasia 
ossificans progressiva. J. Biol. Chem., 287, pp. 36990-8.

Mohedas AH, Wang Y, Sanvitale CE, Canning P, Choi S, Xing X, Bullock AN, Cuny 
GD, Yu PB. (2014). Structure-activity relationship of 
3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity 
for fibrodysplasia ossificans progressiva causing mutants. J. Med. Chem., 57, 
pp. 7900-15.

Chaikuad A, Bullock AN. (2016). Structural Basis of Intracellular TGF-β 
Signaling: Receptors and Smads. Cold Spring Harb Perspect Biol, [Epub]

Taylor KR, Vinci M, Bullock AN, Jones C. (2014). ACVR1 mutations in DIPG: 
lessons learned from FOP. Cancer Res., 74, pp. 4565-70.

Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel 
D, Grasso CS, Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, 
Entz-Werle N, Ingram WJ, Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones 
C, Grill J. (2014). Recurrent activating ACVR1 mutations in diffuse intrinsic 
pontine glioma. Nat. Genet., 46, pp. 457-61.

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