7z5x | pdb_00007z5x
ROS1 with AstraZeneca ligand 2
Structural highlights
DiseaseROS1_HUMAN Note=A chromosomal aberration involving ROS1 is found in a glioblastoma multiforme sample. An intra-chromosomal deletion del(6)(q21q21) is responsible for the formation of GOPC-ROS1 chimeric protein which is localized to the Golgi and has a constitutive receptor tyrosine kinase activity. A SLC34A2-ROS1 chimeric protein produced in non-small cell lung cancer cells also retains a constitutive kinase activity. A third type of chimeric protein CD74-ROS1 was also identified in those cells.[1] FunctionROS1_HUMAN Orphan receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2.[2] [3] Publication Abstract from PubMedROS1 rearrangements account for 1-2% of non-small cell lung cancer patients, yet there are no specifically designed, selective ROS1 therapies in the clinic. Previous knowledge of potent ROS1 inhibitors with selectivity over TrkA, a selected antitarget, enabled virtual screening as a hit finding approach in this project. The ligand-based virtual screening was focused on identifying molecules with a similar 3D shape and pharmacophore to the known actives. To that end, we turned to the AstraZeneca virtual library, estimated to cover 10(15) synthesizable make-on-demand molecules. We used cloud computing-enabled FastROCS technology to search the enumerated 10(10) subset of the full virtual space. A small number of specific libraries were prioritized based on the compound properties and a medicinal chemistry assessment and further enumerated with available building blocks. Following the docking evaluation to the ROS1 structure, the most promising hits were synthesized and tested, resulting in the identification of several potent and selective series. The best among them gave a nanomolar ROS1 inhibitor with over 1000-fold selectivity over TrkA and, from the preliminary established SAR, these have the potential to be further optimized. Our prospective study describes how conceptually simple shape-matching approaches can identify potent and selective compounds by searching ultralarge virtual libraries, demonstrating the applicability of such workflows and their importance in early drug discovery. Virtual Screening in the Cloud Identifies Potent and Selective ROS1 Kinase Inhibitors.,Petrovic D, Scott JS, Bodnarchuk MS, Lorthioir O, Boyd S, Hughes GM, Lane J, Wu A, Hargreaves D, Robinson J, Sadowski J J Chem Inf Model. 2022 Aug 3. doi: 10.1021/acs.jcim.2c00644. PMID:35920716[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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