The discovery of rearranged fusions of the anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) was a major breakthrough in targeted molecular therapy. ALK-driven NSCLC is effectively treated with crizotinib.1 ROS1 shares high sequence homology with ALK kinase, with a striking 70% sequence homology at the binding site. Oncogenic fusions of ROS1 have recently been reported as a validated drug target in a number of malignancies including NSCLC and glioblastoma. Accordingly, crizotinib has been used clinically to treat rearranged ROS1-positive NSCLC.2 However, a mutation in the ROS1 kinase domain (G2032R) close to the ATP binding site was detected in a patient exhibiting resistance to crizotinib.3 We reported that foretinib overcomes the ROS1-G2032R mutation.4 Of note, foretinib exhibits weak inhibitory activity toward ALK kinase. Given the structural similarity between ROS1 and ALK kinase, we sought biophysical insights into the differential affinity of these inhibitors, and in particular, the structural plasticity of ROS1 kinase. Explicit solvent simulations of native and mutant ROS1 and ALK kinase (total of 9 µs) reveal conformational changes in the P-loop and the surrounding regions that are detrimental to crizotinib binding and also explain the selectivity observed with foretinib based on ensemble docking and free energy calculations. Careful examination of simulations suggests that foretinib binds via a conformational selection process followed by an induced fit mechanism that optimizes the enzyme-inhibitor interaction. Our studies will play a crucial role in future drug discovery research by incorporating receptor flexibility into virtual screening algorithms used to identify novel inhibitor scaffolds. 1. Shaw, A.T. et al., Lancet Oncol 12, 1004-12 (2011). 2. Shaw, A.T. et al., N Engl J Med (2014) DOI: 10.1056/NEJMoa1406766 3. Awad, M.M. et al., N Engl J Med 368, 2395-401 (2013). 4. Davare, M.A. et al., Proc Natl Acad Sci U S A 110, 19519-24 (2013).

Structural insight into ROS1/ALK kinase conformational dynamics

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.