2014 AACR: SGI-110 DNA HMA SGI-110 reverses Platinum resistance of ovarian cancer models

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Summary

  • Patients with advanced stage ovarian cancer (OC) have a 5-year survival rate of less than 25%. The most common treatment strategy comprises debulking surgery followed by platinum-based chemotherapy. Patients commonly respond to first-line chemotherapy, but >70% relapse, developing platinum-resistance.
  • There is evidence that the acquisition of platinum resistance is associated with the epigenetic silencing of specific genes by DNA methylation.
  • SGI110 is a novel second generation DNA hypomethylating agent, which is  currently in a Phase II clinical trial in combination with carboplatin, in platinumresistant recurrent ovarian cancer patients (NCT01696032).
  • SGI110 is a dinucleotide of decitabine and deoxyguanosine, which is resistant to modification by cytidine deaminase: a common pathway of decitabine metabolism and deactivation.
  • Here we demonstrate that SGI110 reverses the cisplatin-resistance of the A2780 OC model, by abrogating the epigenetic silencing of MLH1. We demonstrate SGI110 activity in a panel of OC cell lines. We suggest that epigenetic silencing of ZIC1 is a mechanism of cisplatin resistance in the OAW28 and Ovcar8 cells and demonstrate that it is reversed by SGI110.

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2014 AACR: SGI-110 DNA HMA SGI-110 reverses Platinum resistance of ovarian cancer models

2014: ESMO Phase 1/2 of AT13387, HSP90 Inhibitor, in combo with abiraterone acetate and prednisone

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Summary

Heat Shock Protein 90 (HSP90) is an ATP-dependent molecular chaperone that assists in correct folding Of a Wide variety Of ‘client’ proteins (Androgen Receptor (AR), AKT, HER2 and CDK4).

ATI 3387 (AT) is a fragment derived, second-generation novel potent non-ansamycin HSP90 inhibitor (Kd:O.71 nM)1 with good tissue distribution, excellent in vivo anti-tumor activity and long tumor half life in preclinical models (65-78 hours).

ATI 3387 demonstrated anti-tumor activity in preclinical castration-resistant prostate cancer (CRPC) models2 and ho ds promise as a therapeutic agent by simultaneously down-regulating multiple aberrant signalling pathways.

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2014: ESMO Phase 1/2 of AT13387, HSP90 Inhibitor, in combo with abiraterone acetate and prednisone

2014 AACR: AT13387 combined with erlotinib improves response in EGFR-driven xenograft models of NSCL

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Summary

Epidermal Growth Factor Receptor (EGFR) can be activated by point mutations e.g L858R or by deletions in exon19. A subset of non-small cell lung cancer (NSCLC) have activated EGFR and can be successfully treated with EGFR inhibitors such as erlotinib. However, resistance frequently develops to these inhibitors, often due to acquisition of a further T790M mutation in EGFR leading to relapse. Methods to improve response and delay resistance are therefore of value.

Inhibition of the chaperone, HSP90, leads to the depletion of many client proteins, including EGFR, and has the capacity to simultaneously affect many signalling pathways, offering an alternative strategy for targeting EGFR-driven disease.

AT13387 is a potent, second generation HSP90 inhibitor currently being tested in Phase 2 clinical trials. Here we investigated the effects of combining AT13387 and erlotinib in models of EGFR- driven NSCLC.

2014 AACR: AT13387 combined with erlotinib improves response in EGFR-driven xenograft models of NSCL

2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models

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Summary

The inhibitor of apoptosis proteins (IAPs) are widely de-regulated in many tumours and contribute to cancer drug resistance. The targeted inhibition of IAPs can switch TNF-alpha
signaling in cancer cells from pro-survival to pro-apoptotic. Therefore, IAPs represent an attractive target for cancer therapy.
The IAP family member cellular IAP1 (cIAP1) is involved in the regulation of TNF-alpha signaling and X-linked IAP (XIAP) directly interacts with and inhibits caspases. IAP family members are
characterized by BIR (baculoviral IAP repeat) domains, to which the endogenous inhibitor of IAPs SMAC (second mitochondria derived activator of caspases) binds. Peptidomimetic compounds
based on the SMAC sequence have been developed, but they show high selectivity for cIAP1. We used our fragment based-drug discovery approach to generate a non-alanine, nonpeptidomimetic
IAP antagonist, which has dual potency for XIAP and cIAP1. Here we describe the characterization of this compound in in vitro and in vivo models of melanoma and breast cancer.
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2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models

2014 TAT: HSP90 inhibition by AT13387 can overcome & delay appearance of resistance to TKI in lung

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2014 TAT: HSP90 inhibition by AT13387 can overcome & delay appearance of resistance to TKI in lung

2014 CPTT. Novel Small Molecule Antagonists of XIAP and cIAP Generated by Fragment-based Drug Discovery

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Summary

The inhibitor of apoptosis proteins (IAPs) are widely de-regulated in many tumours and contribute to cancer drug resistance. The targeted inhibition of IAPs can switch TNF-alpha
signaling in cancer cells from pro-survival to pro-apoptotic. Therefore, IAPs represent an attractive target for cancer therapy.
The IAP family member cellular IAP1 (cIAP1) is involved in the regulation of TNF-alpha signaling and X-linked IAP (XIAP) directly interacts with and inhibits caspases. IAP family members are
characterized by BIR (baculoviral IAP repeat) domains, to which the endogenous inhibitor of IAPs SMAC (second mitochondria derived activator of caspases) binds. Peptidomimetic compounds
based on the SMAC sequence have been developed, but they show high selectivity for cIAP1. We used our fragment based-drug discovery approach to generate a non-alanine, nonpeptidomimetic
IAP antagonist, which has dual potency for XIAP and cIAP1. Here we describe the characterization of this compound in in vitro and in vivo models of melanoma and breast cancer.

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2014 CPTT. Novel Small Molecule Antagonists of XIAP and cIAP Generated by Fragment-based Drug Discovery

2013 ASH: First Clinical Results of a randomized Phase 2 study of SGI-110 in adult patients with AML

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2013 ASH: First Clinical Results of a randomized Phase 2 study of SGI-110 in adult patients with AML

2013 ASH: Determinants of Demethylation and Clinical Response in AML patients treated with SGI-110

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2013 ASH: Determinants of Demethylation and Clinical Response in AML patients treated with SGI-110

2013 WorldMelanoma: Combining AT13387 with vemurafenib delay emergence of resistance in preclin mode

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2013 WorldMelanoma: Combining AT13387 with vemurafenib delay emergence of resistance in preclin mode

2013 ASH: Preclin Data in Cynomologus Monkeys of ASTX727, an oral HMA composed of decitabine & E7727

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2013 ASH: Preclin Data in Cynomologus Monkeys of ASTX727, an oral HMA composed of decitabine & E7727