MedKoo product information:

AT13387

Description of AT13387: AT13387 is a synthetic, orally bioavailable, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp90 inhibitor AT13387 selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Astex Therapeutics Inc. 

AT13387 shows activity against a wide array of tumor cell lines including lung cancer cell lines. AT13387 induced the degradation of specific HSP90 client proteins for up to 7 days in tumor cell lines in vitro. Pharmacokinetic analyses indicated that although AT13387 was rapidly cleared from blood while its retention in tumor xenografts was markedly extended. AT13387 was efficacious in a range of xenograft models and the long duration of action allowed the efficacious once weekly administration of AT13387 in human lung carcinoma xenografts.  (source: Cancer Sci. 2011 Dec 19. doi: 10.1111/j.1349-7006.2011.02191.x. [Epub ahead of print]).

Cell-based activity of AT13387

AT13387 is a potent inhibitor of HCT116 cell proliferation. Following 72 h of exposure, it potently inhibited the proliferation of a panel of human tumor cell lines (well over 100 cell lines have been tested), showing IC50<100 nM against more than 50.  The in vitro activity data of AT13387 reported recently can be summarized as the following:

Kd (HSP90 ) = 0.71 nM ,

IC50 (HCT116) = 48 nM;

logD (pH 7.4) = 2.7;

pKa (amine) = 7.7.

hErG % inhibition 7% (drug concentration = 3 µM) and  42% (drug concentation = 30 µM). 

[source: J. Med. Chem.  2010, 53(16):  5956-5969.]

PK Study of AT13387

The plasma clearance of AT13387 in femaleBALB/c mice after iv dosing ranged from 113 to
200 (mL/min)/kg with a half-life of between 0.9 and 3.2 h. Volume of distribution was 11-13 L/kg.  The tissue distribution ofAT13387 was shown to have a half-life in HCT116 tumors of 65 h and a tumor concentration of 9.3 μM after 24 h.  Encouragingly AT13387 showed some oral bioavailability
in mouse (31%) despite the high plasma clearance (113-200 (mL/min)/kg). Protein binding inmouse plasma was 91%. [source: J. Med. Chem.  2010, 53(16):  5956-5969.]

In vivo antitumor activity of AT13387

AT13387  was evaluated for its in vivo antitumor activity in nudeBALB/cmice bearing early stage HCT116 human colon carcinoma xenografts with amean starting volume of approximately 100mm3. In this study the L-lactate salt of AT13387 , dissolved in 17.5% hydroxypropyl-β-cyclodextrin was administered by the ip route using a repeated cycle of dosing of once per day for 3 days, no dose for 3 days, for four dosing cycles. Tumor growth inhibition at the end of the dosing phase (day 21) was 78% for the 60 mg/kg dose level (%T/C=22). Animals were monitored for tumor regrowth after cessation of dosing, and a tumor growth delay of 17 days was observed for this dosing schedule.  [source: J. Med. Chem.  2010, 53(16):  5956-5969.]

Status of research and development

AT13387  is currently being developed by Astex Therapeutic.  In vitro, AT13387 is an extremely potent inhibitor of Hsp90, and inhibits the growth and survival of a broad range of cell lines derived from different human tumors. AT13387 suppresses the levels of key oncogenic proteins such as the androgen receptor, erbB2, EGFr and BRaf in cell lines derived from patients with some of our targeted indications. AT13387 also inhibits tumor growth in multiple xenograft models and confirmed mechanism-based efficacy via suppression of key oncogenic proteins in these models. The preclinical toxicology programme has shown AT13387 to be well tolerated. Although designed for intravenous delivery, AT13387 has also demonstrated oral bioavailability. AT13387 is currently being investigated in an initial "oligo-specific" Phase I study in patients with a limited range of tumor types. This study, which is investigating two different dosing schedules is being conducted at multiple sites in the USA. The study is designed to assess the safety and tolerability of AT13387 in patients with advanced refractory solid tumours, and via the selection of patients who are more likely to respond to Hsp90 inhibitor therapy. The study is also intended to provide early evidence of clinical efficacy. In November 2009, Astex entered into a CRADA with the US National Cancer Institute (NCI) to support the further clinical development of AT13387 over the next 5 years with a number of single agent and combination Phase I/IIa and Phase II studies planned. (source: http://astx.com/pipeline/products/clinical#at13387). 

1: Graham B, Curry J, Smyth T, Fazal L, Feltell R, Harada I, Coyle J, Williams B, Reule M, Angove H, Cross DM, Lyons J, Wallis NG, Thompson NT. The HSP90 Inhibitor, AT13387, Displays a Long Duration of Action In vitro and In vivo in non-small cell lung cancer. Cancer Sci. 2011 Dec 19. doi: 10.1111/j.1349-7006.2011.02191.x. [Epub ahead of print] PubMed PMID: 22181674.

2: Liu J, Wang F, Ma Z, Wang X, Wang Y. Structural Determination of Three Different Series of Compounds as Hsp90 Inhibitors Using 3D-QSAR Modeling, Molecular Docking and Molecular Dynamics Methods. Int J Mol Sci. 2011 Jan 30;12(2):946-70. PubMed PMID: 21541036; PubMed Central PMCID: PMC3083683.

3: Kang MH, Reynolds CP, Houghton PJ, Alexander D, Morton CL, Kolb EA, Gorlick R, Keir ST, Carol H, Lock R, Maris JM, Wozniak A, Smith MA. Initial testing (Stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program. Pediatr Blood Cancer. 2011 Apr 29. doi: 10.1002/pbc.23154. [Epub ahead of print] PubMed PMID: 21538821; PubMed Central PMCID: PMC3154460.

4: Maurer T. Advancing fragment binders to lead-like compounds using ligand and protein-based NMR spectroscopy. Methods Enzymol. 2011;493:469-85. PubMed PMID: 21371602.

5: Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydrois oindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem. 2010 Aug 26;53(16):5956-69. PubMed PMID: 20662534.

Patents related to AT-13387

1. Pharmaceutical N-benzoyldihydroisoindole compounds as HSP-90 modulators and their preparation and use in the treatment of diseases By Williams, Brian John; Williams, Marian; Frederickson, Martyn From U.S. Pat. Appl. Publ. (2011), US 20110098290 A1 20110428.

2. Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design By Woodhead, Andrew J.; Angove, Hayley; Carr, Maria G.; Chessari, Gianni; Congreve, Miles; Coyle, Joseph E.; Cosme, Jose; Graham, Brent; Day, Philip J.; Downham, Robert; et al From Journal of Medicinal Chemistry (2010), 53(16), 5956-5969.

3. Preparation of isoindolyl phenyl methanone derivs. for treating and preventing HSP90-mediated diseases By Williams, Brian John; Frederickson, Martyn From PCT Int. Appl. (2009), WO 2009125230 A1 20091015.

4. Preparation of N-benzoylisoindoline derivatives and analogs as analgesics By Congreve, Miles Stuart; Fazal, Lyndsey Helen; Frederickson, Martyn; Murray, Christopher William; O'Brien, Michael Alistair; Woodhead, Andrew James; Lyons, John Francis; Thompson, Neil Thomas From PCT Int. Appl. (2008), WO 2008044027 A2 20080417.

5. Preparation of hydrobenzamide derivatives as inhibitors of HSP90 By Frederickson, Martyn; Lyons, John Francis; Thompson, Neil Thomas; Vinkovic, Mladen; Williams, Brian; Woodhead, Andrew James; Woolford, Alison Jo-Anne From PCT Int. Appl. (2008), WO 2008044034 A1 20080417.

6. Preparation of N-benzoylisoindoline derivatives and analogs as analgesics By Lyons, John Francis; Thompson, Neil Thomas From PCT Int. Appl. (2008), WO 2008044054 A2 20080417.

7. Preparation of N-benzoylisoindoline derivatives and analogs as analgesics By Gallagher, Neil James; Lyons, John Francis; Thompson, Neil Thomas; Yule, Stephen Murray; Murray, Christopher William From PCT Int. Appl. (2008), WO 2008044045 A1 20080417.

8. Preparation of N-benzoylisoindoline derivatives and analogs as analgesics By Gallagher, Neil James; Lyons, John Francis; Thompson, Neil Thomas; Yule, Stephen Murray; Murray, Christopher William From PCT Int. Appl. (2008), WO 2008044029 A1 20080417.

9. Preparation of N-benzoylisoindoline derivatives and analogs as analgesics By Gallagher, Neil James; Lyons, John Francis; Thompson, Neil Thomas; Yule, Stephen Murray; Murray, Christopher William From PCT Int. Appl. (2008), WO 2008044041 A1 20080417.

10. Preparation of hydroxybenzamides as Hsp90 inhibitors By Chessari, Gianni; Congreve, Miles Stuart; Figueroa Navarro, Eva; Frederickson, Martyn; Murray, Christopher; Woolford, Alison Jo-Anne; Carr, Maria Grazia; Downham, Robert; O'Brien, Michael Alistair; Phillips, Theresa Rachel; et al From PCT Int. Appl. (2006), WO 2006109085 A1 20061019.