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HitGen announces collaboration in drug discovery with the University of Manchester’s Cancer Research UK Manchester Institute and CRT

On November 8, 2013 HitGen Ltd reported that it has entered into a research collaboration with The University of Manchester’s Cancer Research UK Manchester Institute Drug Discovery Group and Cancer Research Technology using HitGen’s proprietary lead discovery technology (Press release, Cancer Research Technology, AUG 8, 2013, View Source [SID1234523247]). Within the framework of the collaboration, hundreds of millions of small molecules will be screened to discover and advance drug candidates against multiple new oncology targets of interest to the Cancer Research UK Manchester Institute.

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HitGen’s encoded libraries have been designed to contain many hundreds of millions of small molecules with drug-like properties and have been synthesized on many chemically diverse scaffolds in order to provide maximum opportunity for finding drug leads against protein targets from known and novel protein classes.

Under the terms of the agreement the Cancer Research UK Manchester Institute will provide HitGen with funding for collaborative research and success-based milestone payments as candidate molecules progress through preclinical testing and into clinical development. Further financial details were not disclosed.

"We are very pleased to initiate our research partnerships by entering into this drug discovery collaboration with the Cancer Research UK Manchester Institute, a world leading cancer research group." said Dr Jin Li, CEO of HitGen Ltd. "We are looking forward to successfully tackling challenging targets using this cutting edge technology in collaboration with the innovative scientists at the Cancer Research UK Manchester Institute."

"We are very excited by this collaboration; HitGen’s technology offers us a novel way of prosecuting cancer targets derived from Cancer Research UK funded research" said Dr Donald Ogilvie, Head of the Drug Discovery Unit at the Cancer Research UK Manchester Institute. "We anticipate that this will allow us to tackle targets which have not been amenable to more traditional hit finding methods". He went on to say that "in the longer term we hope that this collaboration will allow us to deliver real patient benefit to the global cancer community."

"This important collaboration will allow us to access a library of millions of compounds enabling us to develop new ways to block challenging targets. This agreement will pave the way for new treatments and new options for patients which we hope ultimately will one day save more lives from cancer" said Dr Phil L’Huillier, Director of Business Development at CRT.

Curis Reports Third Quarter 2013 Financial Results and Provides CUDC-427 Development Update

On November 5, 2013, the Company received written notification from the United States Food and Drug Administration (FDA) that its Phase 1 study of CUDC-427 has been placed on partial clinical hold following the report of death of a patient who progressed to liver failure approximately one month following the discontinuation of CUDC-427 dosing (Press release Curis, NOV 6, 2013, View Source [SID:1234500346]). Under this partial clinical hold, new patients may not be enrolled in the study until Curis provides the FDA with requested additional data and analysis on patients treated with CUDC-427 and a proposed protocol amendment is submitted to and accepted by the FDA. The Company expects to respond to the FDA’s requests for additional information and also plans to submit an amendment to the current protocol in a timely manner.
The current open-label, single-agent, dose escalation Phase 1 study of CUDC-427 was initiated in the third quarter of 2013 in patients with advanced and refractory solid tumors or lymphomas. The study was designed to determine the maximum tolerated dose (MTD) and recommended single-agent Phase 2 dose of CUDC-427 using a continuous, twice-daily treatment schedule. One patient with breast cancer metastatic to the liver, lungs, bone and ovaries developed serious adverse events related to liver function, including increases in serum levels of AST and ALT enzymes and bilirubin. Unlike prior clinical experience with CUDC-427, this patient’s liver enzyme levels did not recover in response to CUDC-427 discontinuation, and the patient died of liver failure approximately one month following the discontinuation of CUDC-427 dosing. While elevations in liver enzyme levels have previously occurred in patients receiving CUDC-427, no other patients in this or a prior Phase 1 CUDC-427 trial have experienced a serious adverse event of this nature. There are no patients currently being treated with CUDC-427 in this study as all other patients enrolled in this study have discontinued dosing due to disease progression or patient or physician discretion during the ordinary course of the study.

Cancer Research Technology and Nuevolution sign multi-target deal to seek potential cancer drugs

On November 4, 2013 Cancer Research Technology (CRT), the commercial arm of Cancer Research UK, and Denmark-based drug discovery company Nuevolution A/S, reported to have signed a collaboration deal to discover anti-cancer drug molecules targeting several key proteins (Press release, Cancer Research Technology, APR 4, 2013, View Source [SID1234523248]).

The collaboration aims to identify drug leads that block the activity of a number of challenging cancer therapeutic targets. This could lead to the development of first-in-class novel treatments for cancer patients.

Through the partnership, drug candidate molecules which home in on selected targets will be identified by screening millions of diverse small molecules using Nuevolution’s proprietary Chemetics technology. This uses innovative DNA labelling to enable small molecule drug screening – a method to identify small molecules which bind to a target protein – on an unprecedented scale.

Thomas Franch, CSO of Nuevolution, said: "We are delighted to enter into this collaboration and believe that a strong synergy between the CRT and Nuevolution capabilities will provide for discovery traction on tough-to-drug targets.

CRT will provide expert information about the biology of the targets through Cancer Research UK’s network of world-class scientists. The first targets have already been approved by CRT and Nuevolution for entry into the collaboration.

In addition, CRT through its internal Discovery Laboratories will provide drug discovery expertise including in-vitro screening assays and cellular activity assays for the target proteins, to select the most promising molecules to develop as potential drugs.

The further pre-clinical development of any promising small molecules identified will form the basis of a separate deal to be agreed in the future between CRT and Nuevolution.

Dr Hamish Ryder, director of drug discovery at CRT’s Discovery Laboratories, said: "This deal is exciting as it will allow us to address a number of "low-tractability" cancer targets, which have proved difficult for ourselves and others to establish a foothold in drug discovery".

"This important partnership combines CRT’s drug discovery expertise and Cancer Research UK’s strong academic research base with powerful technology from Nuevolution to enable 100s of millions of compounds to be rapidly assessed – which we hope one day will be a starting point for new options for cancer patients and increased survival."

Nimbus Discovery Advances Broad Portfolio of ACC Inhibitors for Potential Treatment of Diabetes, NASH and Liver Cancer

On November 1, 2013 Nimbus Discovery reported that it will present preclinical data at The Liver Meeting, the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), that show the company has optimized a unique series of Acetyl Co-A Carboxylase (ACC) allosteric inhibitors that bind to the BC domain of ACC and demonstrate excellent potency, drug-like properties and preclinical efficacy (Press release Nimbus Discovery, NOV 1, 2013, View Source [SID:1234501248]). The novel, internally-developed small molecules, ND-654 and ND-630, demonstrated desirable in vitro and in vivo efficacy in experimental models of metabolic disease, diabetes and hepatic steatosis. In an iterative design fashion over 16 months, the potency of this family of compounds were improved >1000x utilizing the company’s proprietary small molecule computational drug discovery technology, and drug-like properties were optimized to efficiently deliver development candidate quality molecules.

Simultaneous inhibition of both isoforms of ACC decreases fatty acid synthesis and stimulates fatty acid oxidation and has the potential to favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver diseases including non-alcoholic steatohepatitis (NASH). Nimbus’ ACC inhibitors, including ND-654 and ND-630, are believed to be the first drug-like allosteric inhibitors to bind the biotin carboxylase (BC) domain of ACC with high potency and selectivity.

Key findings of the Nimbus compounds presented at the conference include:

ND-654
Liver specific ND-654 has favorable drug-like properties with a 2700:1 liver to muscle exposure
Proof-of-mechanism: ND-654 acutely inhibits ACC, with virtually no effect on muscle, resulting in focused pharmacological effects on the liver
Proof-of-concept: ND-654 demonstrated target engagement in the liver and dose dependently decreased fatty acid production in the liver
NC-630
Liver selective ND-630 has favorable drug-like properties with a 100:1 liver to muscle exposure
Proof-of-mechanism: ND-630 acutely inhibits ACC, demonstrating efficacy in both liver and muscle by preventing malonyl Co-A production
Proof-of-concept: ND-630 demonstrated target engagement in the liver and muscle
Dosing of ND-630 in high sucrose fed diet-induced obesity (DIO) rats showed improvement in insulin sensitivity, improvement in hepatic cholesterol and normalization of hepatic triglycerides, dose dependent decrease of plasma triglycerides and FFAs, and decrease in plasma cholesterol

"Within 16 months, Nimbus has become the first company to identify and optimize a broad portfolio of liver directed, small molecule inhibitors of ACC — a previously intractable disease target," said Rosana Kapeller, M.D., Ph.D., Chief Scientific Officer of Nimbus. "We are now preparing for ND-630 to enter the clinic in 2015 for the treatment of NASH and diabetes, while we continue to progress ND-654 in preclinical models of hepatocellular carcinoma."

CRT Pioneer Fund collaborates with Chroma Therapeutics to develop cancer drugs targeting the immune system

On October 31, 2013 THE Cancer Research Technology Pioneer Fund (CPF) reported a collaboration with Chroma Therapeutics Ltd to develop cancer drugs targeting macrophages – white blood cells – associated with tumours (Press release, Cancer Research Technology, 31 31, 2013, View Source [SID1234523249]).

This investment by the CPF will accelerate the development of a promising ‘lead’ molecule – taking it from the laboratory into clinical trials for patients.

Chroma has licensed to CPF the rights to further develop and commercialise molecules to target a key mitogen activated protein kinase (p38). Inhibiting p38 activity alters the behaviour of tumour-associated macrophages (TAMs) so that instead of driving tumour growth, the TAMS switch to destroying tumours.

Richard Bungay, chief executive of Chroma, said: "Immuno-modulation is an exciting new field of cancer research and we are delighted to be working with CPF in order to accelerate the evaluation of the unique ability of our ESM technology to target key immune system cells as a new therapeutic approach."

The molecules have been modified to accumulate inside myeloid cells (blood cells) using Chroma’s own Esterase Sensitive Motif (ESM) technology. This technology attaches specific chemical motifs onto drugs, which are freely transported into cells. Once inside the cell, enzymes called esterases remove the motifs to create a compound that cannot easily exit the cell. Over time, the drug accumulates in TAMS, and reprogrammes them to attack tumours.

This is the third investment made by the CPF. It builds on initial research funded by Cancer Research UK and CRT led by Dr Thorsten Hagemann, at Queen Mary University of London, Barts Cancer Institute. This early research proved that the lead molecule, which was designed and synthesised by Chroma, can effectively switch macrophage behaviour to attack a range of cancer types, including lymphoma and pancreatic tumours in laboratory and animal studies.

Cancer Research Technology (CRT), Cancer Research UK’s commercial arm, and the European Investment Fund (EIF) launched the £50m CPF to bridge the UK funding gap between cancer drug discovery and early treatment development and appointed Sixth Element Capital to manage the fund.

Dr Robert James, managing partner of Sixth Element Capital, said: "We’re delighted to announce this collaboration between the CPF and Chroma to progress an innovative new approach to develop cancer drugs. CPF was set up to invest in the most exciting science behind new potential techniques to treat cancer, such as this."

Dr Keith Blundy, chief executive of Cancer Research Technology, said: "We’re extremely pleased to announce this innovative partnership, which will take forward the work done by Cancer Research UK-funded scientists and Chroma from the laboratory into clinical trials. Ultimately we hope this collaboration will produce potential new cancer drugs to improve survival for cancer patients."