Discovery of novel aminoquinazolin-7-yl 6,7-dihydro-indol-4-ones as potent, selective inhibitors of heat shock protein 90 Kenneth H. Huang  ,⇑ , Thomas E. Barta, John W. Rice, Emilie D. Smith, Andy J. Ommen, Wei Ma, James M. Veal, R. Patrick Fadden, Amy F. Barabasz, Briana E. Foley, Philip F. Hughes, Gunnar J. Hanson, Christopher J. Markworth, Melanie Silinski, Jeffrey M. Partridge, Paul M. Steed, Steven E. Hall Serenex Inc., 323 Foster Street, Durham, NC 27701, USA article info Article history: Received 8 August 2011 Revised 29 January 2012 Accepted 31 January 2012 Available online 15 February 2012 Keywords: Hsp90 Chaperone Inhibitors Indolone Aminoquinazoline Quinazoline Her2 Cancer abstract A novel class of Hsp90 inhibitors, structurally distinct from previously reported scaffolds, was developed from rational design and optimization of a compound library screen hit. These aminoquinazoline derivatives, represented by compound 15 (SNX-6833) or 1-(2-amino-4-methylquinazolin-7-yl)-3,6,6- trimethyl-6,7-dihydro-1H-indol-4(5H)-one, selectively bind to Hsp90 and inhibit its cellular activities at concentrations as low as single digit nanomolar. Ó 2012 Elsevier Ltd. All rights reserved. Heat shock protein 90 (Hsp90) has received significant atten- tion as a therapeutic target for cancer treatment. 1 Hsp90 acts as a molecular chaperone that aids the folding, 2 maturation, trans- port, and maintenance of conformational stability of its client pro- teins. 3 Many of these client proteins are involved in critical cellular functions that promote cell growth, proliferation and survival, and are also themselves being pursued as anti-cancer targets, for exam- ple, Her2, c-Met, and Cdk-4 as well as a wide range of mutated pro- teins. 4 Hsp90 is also over-expressed in malignant cells thus these cells may be more dependent on the Hsp90 chaperoning function. 5 Targeting Hsp90 blocks multiple oncogenic signaling pathways, 3 thus diminish the potential for resistance to Hsp90 inhibitors. 6 Inhibition of Hsp90 N-terminal domain ATPase activity 7 disrupts an ongoing ‘folding’ cycle, leads to destabilization, ubiquitination, and ultimately proteasomal degradation of client proteins. 6 The natural products geldanamycin 8 and radicicol 9 are inhibitors of Hsp90. More recently, additional classes of Hsp90 inhibitors have been developed. 10–14 Here we report our synthetic and medicinal chemistry efforts in the discovery of a novel aminoquinazoline scaffold that inhibits Hsp90. 15 Through screen of a focused compound library against sets of ATP binding proteins, we identified 4-(2,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide (1, Fig. 1) as a moder- ate hit for Hsp90 binding (K d = 3.7 lM), although it was inactive in multiple cellular assays (IC 50 >50 lM). 13 Structure-based design led us to synthesize 1-(4-aminoquinazoline-7-yl)-2,6,6-trimethyl- 6,7-dihydro-1H-indol-4(5H)-one (2), which showed improved activity in an Her2 degradation assay (SKBR3 cells; IC 50 = 10 lM). This scaffold appears not only small but also drug-like: both its 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2012.01.137 ⇑ Corresponding author. E-mail address: khuang@pamlicopharma.com (K.H. Huang).   Present address: Pamlico Pharmaceutical Inc., PO Box 110284, 7020 Kit Creek Road Suite 180, Research Triangle Park, NC 27709, USA. N O H 2 N 1 O N N H 2 N 2 O N Figure 1. Two related Hsp90 inhibitors: an initial screen hit benzamide 1, and a 4-aminoquinazoline 2 with a variant cyclic binding head. Bioorganic & Medicinal Chemistry Letters 22 (2012) 2550–2554 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl