Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: Potent inhibitors of the IGF-1R receptor tyrosine kinase Stanley D. Chamberlain a , Joseph W. Wilson a , Felix Deanda b , Samarjit Patnaik a , Anikó M. Redman a , Bin Yang a , Lisa Shewchuk b , Peter Sabbatini c , M. Anthony Leesnitzer d , Arthur Groy c , Charity Atkins c , Roseanne Gerding a , Anne M. Hassell b , Huangshu Lei a , Robert A. Mook Jr. a , Ganesh Moorthy c , Jason L. Rowand c , Kirk L. Stevens a , Rakesh Kumar c , J. Brad Shotwell a, * a GlaxoSmithKline, Oncology R&D, 5 Moore Drive, 3.4184.4B, PO Box 13398, Research Triangle Park, NC 27709-3398, USA b GlaxoSmithKline, Computational and Structural Chemistry, 5 Moore Drive, Research Triangle Park, NC 27709, USA c GlaxoSmithKline, Oncology R&D, 1250 S. Collegeville Road, Collegeville, PA 19426, USA d GlaxoSmithKline, Molecular Discovery Research, 5 Moore Drive, Research Triangle Park, NC 27709, USA article info Article history: Received 8 October 2008 Revised 8 November 2008 Accepted 12 November 2008 Available online 18 November 2008 Keywords: Pyrrolopyrimidine IGF-1R Kinase inhibitor IGF-IR abstract The evaluation of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Examples demonstrate nanomolar potencies in in vitro enzyme and mechanistic cellular assays as well as promising in vivo pharmacokinetics in rat. Ó 2008 Elsevier Ltd. All rights reserved. The IGF-1R signaling pathway is activated in many human can- cers including prostate, 1 colon, 2 breast, 3 and pancreas 4 by overex- pression of IGF-1R or its ligands IGF-1 and 2 and/or by decreased levels of IGF binding proteins. Inhibition of IGF-1R signaling using a variety of approaches (e.g., anti-IGF-1R antibodies, antisense, IGF binding proteins, siRNA) has resulted in decreased proliferation and survival of tumor cells in vitro and in vivo. 5 Further, IGF-1R activation has been associated with resistance to targeted agents such as trastuzumab 6 in breast cancer. Therefore, inhibition of IGF-1R signaling may reverse resistance to targeted agents under certain conditions. These observations have led to the development of a number of potent small-molecule inhibitors of IGF-1R in diverse chemical space. 7 We report herein the investigation of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines, whose syn- theses have been described elsewhere, 8 as potent inhibitors of the IGF-1R receptor tyrosine kinase. Pyrrolopyrimidine 1 was identified from a focused library con- sisting of small molecules with known kinase inhibitory motifs. A remarkable kinase selectivity profile was observed for 1, wherein 48 of 52 kinases screened in the initial panel showed IC 50 values of >100 nM (50-fold selectivity relative to IGF-1R). However, in addition to IGF-1R, pyrrolopyrimidine 1 also potently inhibited JNK1, ALK, and IR, with IC 50 s of 12, 1.0, and 6.3 nM, respectively. 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.11.046 * Corresponding author. E-mail address: JBS26900@GSK.com (J.B. Shotwell). Figure 1. Model of IGF-1R (carbon atoms in grey) in complex with 1 (carbon atoms in green). Intermolecular H-bond interactions are highlighted with yellow lines. Bioorganic & Medicinal Chemistry Letters 19 (2009) 469–473 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl