title: Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches.
abstract: PRP4 kinase is known for its roles in regulating pre-mRNA splicing and beyond. Therefore, a wider spectrum of PRP4 kinase substrates could be expected. The role of PRP4 kinase in cancer is also yet to be fully elucidated. Attaining specific and potent PRP4 inhibitors would greatly facilitate the study of PRP4 biological function and its validation as a credible cancer target. In this report, we verified the requirement of enzymatic activity of PRP4 in regulating cancer cell growth and identified an array of potential novel substrates through orthogonal proteomics approaches. The ensuing effort in structural biology unveiled for the first time unique features of PRP4 kinase domain and its potential mode of interaction with a low molecular weight inhibitor. These results provide new and important information for further exploration of PRP4 kinase function in cancer.
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Tucson Research Center, Sanofi, Tucson, Arizona 85755.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mechin
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Nayantara
authors.initials: N
authors.lastname: Kothari
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Gejing
authors.initials: G
authors.lastname: Deng
authors.affiliation: Lead Generation and Candidate Realization, Sanofi, Bridgewater, New Jersey 08807, and.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Haas
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: McManus
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Hoffmann
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Anlai
authors.initials: A
authors.lastname: Wang
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Wiederschain
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rocnik
authors.affiliation: Lead Generation and Candidate Realization, Sanofi, Industriepark Höchst, 65926 Frankfurt, Germany.
authors.forename: Werngard
authors.initials: W
authors.lastname: Czechtizky
authors.affiliation: Lead Generation and Candidate Realization, Sanofi, Bridgewater, New Jersey 08807, and.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Lead Generation and Candidate Realization, Sanofi, Bridgewater, New Jersey 08807, and.
authors.forename: Larry
authors.initials: L
authors.lastname: McLean
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Heike
authors.initials: H
authors.lastname: Arlt
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: David
authors.initials: D
authors.lastname: Harper
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Lead Generation and Candidate Realization, Sanofi, Waltham, Massachusetts 02451.
authors.forename: Tahir
authors.initials: T
authors.lastname: Majid
authors.affiliation: Lead Generation and Candidate Realization, Sanofi, Waltham, Massachusetts 02451.
authors.forename: Vinod
authors.initials: V
authors.lastname: Patel
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Bailin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: From Discovery and Early Development, Sanofi Oncology, Cambridge, Massachusetts 02139 and 94400 Vitry-sur-Seine Cedex, France,. Electronic address: alex.huang@sanofi.com.
authors.forename: Shih-Min A
authors.initials: SA
authors.lastname: Huang
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D040901:Proteomics / Q000379:methods; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; C489982:PRPF4 protein, human; D047428:Protein Kinase Inhibitors; D017414:Ribonucleoprotein, U4-U6 Small Nuclear
keywords: Cancer Therapy; Crystallography; Drug Discovery; Proteomics; Structural Biology