NTRC presents novel high-throughput screening assay for Arginase I inhibitors for cancer immunotherapy at AACR Annual Meeting in Chicago

NTRC will present two scientific posters at the AACR Annual Meeting 2018, to be held from April 14th to 18th in Chicago. The first poster relates to Arginase, a promising target in the field of cancer immunotherapy. The poster describes a novel high-throughput assay technology that was used to screen for small molecule inhibitors of Arginase I. The screen was performed in collaboration with the Pivot Park Screening Centre.

The second poster relates to targeted therapies and drug response biomarkers. The poster presents the biochemical kinase assay and cell panel profiling data of all kinase inhibitors approved for clinical use. GeneNominator™ gene expression analysis revealed novel drug response biomarkers for BTK and CDK4/6 inhibitors, which will be presented in case studies.

Furthermore, representatives of NTRC will gladly welcome you at booth #1055 in the Exhibition Hall.

Details on the poster presentations are given below:

Title: High-throughput fluorescence-based assay for screening of Arginase I inhibitors for cancer immunotherapy
Presented by: Yvonne Grobben
Session Date and Time: Monday Apr 16, 2018 8:00 am – 12:00 pm
Poster Board Number: 19
Permanent Abstract Number: 1944

Title: Profiling of all clinically approved kinase inhibitors reveals novel drug response biomarkers for BTK and CDK4/6 inhibitors
Presented by: Joost Uitdehaag
Session Date and Time: Tuesday Apr 17, 2018 1:00 pm – 5:00 pm
Poster Board Number: 3
Permanent Abstract Number: 4907

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services, target residence time measurements, and immune oncology assays on a fee-for-service basis. For more information please visit www.ntrc.nl/services or contact services@ntrc.nl

NTRC expands ResidenceTimer™ platform with BTK resistance mutants

Oss, April, 5th, 2018 –NTRC’s ResidenceTimer™ platform enables the determination of the binding kinetics of small molecule kinase inhibitors to their target enzymes. Advantages include: (i) the accurate determination of compound affinity and selectivity; and (ii) the characterization of inhibitor – enzyme interactions in the absence of substrates or co-factors. NTRC has developed ResidenceTimer™ binding assays for more than sixty different protein tyrosine, serine/threonine and lipid kinases. For the popular drug target BTK, four mutant proteins have been added to the portfolio. The BTK mutants correspond to mutations that have been identified as resistance mutants in patients treated with ibrutinib (Imbruvica®) and are T316A, T474I, T474S and C481S. Several companies are developing novel classes of BTK inhibitors that overcome ibrutinib resistance (Figure 1). ResidenceTimer™ assays can be run with activated and non-activated forms of the mutant proteins. Turn-around time is two to three weeks, depending on the number of compounds tested.

Figure 1: Comparison of the binding of ibrutinib (red) and GDC-0853 (blue) to BTK mutated at residue cysteine 418 (BTKC418S). The C418S mutation in BTK underlies the most common mechanism of ibrutinib resistance in the clinic. Overlay of graphs are shown of two single cycle kinetics experiments.

Literature reference

[1] Willemsen-Seegers et al. (2017) Journal of Molecular Biology 429, 574-586
[2] Uitdehaag et al. (2017) Journal of Molecular Biology 429, 2211-2230

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services, target residence time measurements, and immune oncology assays on a fee-for-service basis. For more information please visit www.ntrc.nl/services or contact services@ntrc.nl

NTRC expands SynergyFinder™ platform with triple combination testing

Oss, March, 23rd, 2018 – Many cancer therapies consist of mixtures in which multiple molecular entities work together to halt cancer growth, or to overcome emerging resistance mechanisms. In some cases, as much as five compounds are be combined. Development of such therapy is hampered by the vast number of possible combinations and it is imperative to select candidates in high throughput in vitro experiments, and only to progress the most promising mixtures for further in vivo testing.

            NTRC’s SynergyFinder™ platform allows parallel in vitro screening of combinations and distinguishes additive from synergistic effects [1]. In the past we showed its excellent performance in discovering novel dual combinations [1]. To contribute to the development of cancer therapy that comprises multiple molecular ingredients, NTRC has expanded its SynergyFinder™ platform. In the new setup, mixtures of three can be tested and the individual contribution of each ingredient to the total synergy can be determined. In one such experiment, NTRC has shown that the FDA-approved combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib can be further supplemented with the PI3K inhibitor pictilisib to enhance synergy (Figure 1). By establishing such super-synergistic combinations in vitro, it is possible to effectively focus resources for in vivo studies on the most successful multi-combinations.

 

Figure 1: Example of a triple synergistic combination (grey). Red, yellow and blue indicate dabrafenib, trametinib and pictilisib as single agents, respectively.

Literature reference

[1] Uitdehaag et al. (2015) PLoS ONE 10(5), e0125021

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services, target residence time measurements, and immune oncology assays on a fee-for-service basis. For more information please visit www.ntrc.nl/services or contact services@ntrc.nl

NTRC includes Growth Rate metric evaluation in Oncolines™ profiling

Oss, February, 22nd, 2018 –Compound profiling in cell line panels is a powerful tool in the development of new cancer medicines. Analysis of drug sensitivity across cell lines can reveal response biomarkers in the form of specific genetic mutations or the expression of cancer genes. These response biomarkers can guide subsequent in vivo experiments, and, ultimately, the selection of patients most likely to respond to new drugs in clinical trials. NTRC has set up a panel of 102 cancer cell lines, known as Oncolines™, which enables drug sensitivity analyses and biomarker discovery. The Oncolines™ panel yields highly reproducible data and captures drug response through various metrics [1].

The correct quantification of drug response in cell proliferation assays is the subject of active scientific study. It has been suggested, for instance, that growth rate differences between cell lines may influence IC50 values. To address this, Hafner et al. [2] recently proposed a Growth Rate (GR) metric which quantifies the effect of a drug on growth rate, relative to the growth rate of the untreated cell line. This metric corrects for differences in growth, seeding density and assay time frame, which may confound the comparison of IC50 values. The GR score ranges from 1 (full growth rate) to 0 (cytostasis) to -1 (full growth inhibition) (Figure 1).

To give our users access to this new development, NTRC now includes GR50 and GRmax as optional response metrics in its Oncolines™ 102 cell lines platform, in addition to the regular reporting of IC50, GI50 and LD50 values. Oncolines™ GR50 data can also be used to search for drug response biomarkers via pharmacogenomic analysis. According to Hafner et al. this may lead to biomarkers that are better translatable to in vivo situations [2].

Figure 1. Example of dose-response curves with GR scoring.

Literature references

[1] Uitdehaag et al. (2015) Molecular Cancer Therapeutics 15, 3097-3109.
[2] Hafner et al. (2016) Nature Methods 13, 521-527.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, GeneNominator™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

NTRC at Pivot Oncology conference Breakthroughs in Precision Cancer Treatment

Oss, November, 13th, 2017 – Pivot Park organizes the symposium Breakthroughs in Precision Cancer Treatment on Tuesday November 21st.  As part of the conference, NTRC has organized one of the scientific sessions, entitled ‘Drug discovery: from target to preclinical candidate’. In the session, scientists from NTRC and Lead Pharma will present different aspects of the discovery and development of new precision drug candidates for cancer. The challenges of the different phases of small molecule drug discovery will be described based on real case stories from the drug discovery programs of the two companies.

Program session ‘Drug discovery: from target to preclinical candidate’:

1.30 Opening

1.35 Hit identification and optimization (Lead Pharma)

2.10 Lead optimization and structure-based drug design (NTRC)

2.30 Patient stratification strategies (NTRC)

2.45 Q&A

3.00 End of session

NTRC will also exhibit at the symposium.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, GeneNominator™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

Target residence time-guided lead optimization at the European Pharma Summit in Berlin

Oss, November, 10th, 2017 – At GTC Bio’s European Pharma Summit to be held in Berlin on 16 and 17 November, Dr. Guido Zaman will present on NTRC’s TTK drug discovery program in a scientific session on “Target residence time in kinase drug development”.

Target residence time, that is the time a compound resides on it target, is thought to be a more important determinant of the biological activity of small molecule kinase inhibitors than their potency in enzyme assays, or their binding affinity at equilibrium. Dr. Zaman will present data on twelve TTK inhibitors from different chemical series, comprising NTRC proprietary compounds and compounds designed . Parallel testing showed that the cellular activity of these TTK inhibitors correlates with their binding affinity to TTK and, more strongly, with target residence time. X-ray structures and thermal stability experiments revealed that NTRC’s kinase inhibitor series induce a unique conformational shift in TTK that disrupts its catalytic machinery. This knowledge was applied to design a series of novel TTK inhibitors with unprecedented cellular potency. In addition, Dr. Zaman will present the discovery of a prospective drug sensitivity biomarker for TTK inhibitors using NTRC’s Oncolines™ cell line panel profiling.

Symposium: Kinase inhibitors in drug discovery

Title: Target residence-guided optimization of kinase

Presenter: Dr. Guido Zaman

Date and Time: Thursday, November 16th, 6:40 PM

Literature references:

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

Pharmacogenomic analysis at Molecular Targets and Cancer Therapeutics conference

Oss, October, 16th, 2017 – NTRC will present three scientific posters at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference to be held in Philadelphia (USA) from October 27th to 30th. Two of the posters concern pharmacogenomic analysis of cell proliferation data, one related to NTRC’s TTK kinase inhibitor program; the other on gene expression analysis by GeneNominator™.

 GeneNominator™

Screening of new drugs on large cell panels is an important tool to study the biological mechanism of drug response. NTRC scientists have previously shown that the workflow of Oncolines™ screening leads to highly reproducible IC50s which are necessary for genomic biomarker discovery [1,2]. The IC50 in Oncolines™ profiling experiment have been coupled to curated databases of somatic mutations and copy numbers [1]. However, these changes reflect only a small percentage of oncogenic transformations. A more comprehensive view of oncogenic signalling can be obtained from mRNA expression levels [3]. A workflow to investigate drug response in the 102 cell line Oncolines™ panel based on gene expression levels was developed at NTRC, and applied to determine correlations between cancer cell line sensitivity and gene expression levels of more than 18,000 genes. At the AACR-NCI-EORTC conference case studies will be presented on a protein – protein interaction inhibitor, irreversible EGFR and BTK kinase inhibitors, and drug transporter substrates.

Genomic drug sensitivity biomarker for TTK inhibitors

The spindle assembly checkpoint TTK, also known as Mps1, is a key regulator of chromosome segregation and a promising new drug target for the treatment of cancer. With the aim to identify a genomic biomarker to predict the response of tumour cells to TTK inhibitor therapy, a set of TTK inhibitors from different chemical series [4] was profiled on the Oncolines™ cell line panel [1]. Cell lines harbouring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signalling regulator β-catenin, were up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1 [2]. The association of CTNNB1-mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harbouring either mutant or wild-type CTNNB1. Treatment of a xenograft model of a CTNNB1-mutant cell line with NTRC 1501-0 resulted into tumour regression. Based on these results, mutant CTNNB1 has been proposed as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials

Posters

Combining cell panel screening with analysis of gene expression levels reveals features of drug response and resistance, by Dr. Joost Uitdehaag

Session: Therapeutic Agents: Small-Molecule Kinase Inhibitors; Sunday Oct 29, 2017 12:30 PM – 4:00 PM; Poster Board Number 155, Abstract Number B155

TTK inhibitors as a targeted therapy for CTNNB1 (β-catenin) mutant cancers, by Dr. Guido Zaman

Session: New Molecular Targets; Sunday Oct 29, 2017 12:30 PM – 4:00 PM; Poster Board Number 65, Abstract Number B065

Novel synergistic drug combinations of PARP, bromodomain, and spindle assembly checkpoint kinase inhibitors by large-scale screen of 150 anticancer agents, by Dr. Suzanne van Gerwen

Session: Drug Screening; Saturday Oct 28, 2017 12:30 PM – 4:00 PM; Poster Board Number 153, Abstract Number A153

Meet NTRC Services at booth #815 in the Exhibition Hall of the Pennsylvania Convention Center

Literature references:

[1] Uitdehaag et al. (2016) Cell panel profiling reveals conserved therapeutic clusters and differentiates the mechanism of action of different PI3K/mTOR, Aurora kinase and EZH2 inhibitors. Molecular Cancer Therapeutics 15, 3097-3109.

[2] Zaman et al. (2017) TTK inhibitors as a targeted therapy for CTNNB1 (β-catenin) mutant cancers. Molecular Cancer Therapeutics, advanced online, July 27, 2017.

[3] Rees et al. (2016) Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nature Chemical Biology 12: 109-116.

[4] Uitdehaag et al. (2017) Target residence time-guided optimization on TTK kinase results in inhibitors with potent anti-proliferative activity. Journal of Molecular Biology, 429, 2211-2230.

[5] de Roos et al. Prognostic biomarkers for TTK inhibitor chemotherapy. WO 2016/166255 A1.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

 

Novel synergistic combinations identified by unbiased high-throughput screening

Oss, October, 11th, 2017 – A high-throughput screening approach to identify novel synergistic drug combinations has been launched by NTRC under the name SynergyScreen™. The new service product is available as an extension to NTRC’s cell line profiling on the 102 cancer cell line Oncolines™ panel.

SynergyScreen™

The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. The discovery of new effective drug combinations is constrained by the cost and effort of carrying out large unbiased screens. NTRC scientists have previously shown [1] that curve shift analysis by the approach developed by Straetemans et al. [2] is a more robust method of determining synergy than combination matrix screening using Bliss-scoring. In addition, it shown that NTRC’s workflow for single agent cellular IC50 determination is highly reproducible compared to other workflows [3]. To bring these advantages to bear, and to increase the throughput of identifying new synergistic drug combinations, a two-step approach consisting of screening and confirmation was developed at NTRC.

Combination of PARP inhibitor and topoisomerase inhibitor irinotecan studied by SynergyScreen™ (left) and SynergyFinder™ (right).

NTRC at Molecular Targets and Cancer Therapeutics conference

The screening approach will be presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference, to be held in Philadelphia (USA) from October 27th to 30th. Results will be presented of a SynergyScreen™ with a poly-ADP ribose polymerase (PARP) inhibitor, the BET bromodomain inhibitor JQ1 and inhibitors of the spindle assembly checkpoint.

The poster on SynergyScreen™ will be presented by Dr. Suzanne van Gerwen on Saturday, October 28th, p.m.

Title: Novel synergistic drug combinations of PARP, bromodomain, and spindle assembly checkpoint kinase inhibitors by large-scale screen of 150 anticancer agents

Session Title:                                   Poster Session A

Session Category:                           Drug Screening

Session Date and Time:                  Saturday Oct 28, 2017 12:30 PM – 4:00 PM

Location:                                          Hall E, Pennsylvania Convention Center

Poster Board Number:                    153

Permanent Abstract Number:          A153

Meet NTRC Services at booth #815 in the Exhibition Hall of the Pennsylvania Convention Center

Literature references:

[1] Uitdehaag et al. (2015) Selective targeting of CTNNB1-, KRAS- or MYC-driven tumor cell growth by combinations of existing drugs. PLoS ONE 10(5): e0125021.

[2] Straetemans et al. (2005) Design and analysis of drug combination experiments. Biometrical Journal 47, 299-308.

[3] Uitdehaag et al. (2016) Cell panel profiling reveals conserved therapeutic clusters and differentiates the mechanism of action of different PI3K/mTOR, Aurora kinase and EZH2 inhibitors. Molecular Cancer Therapeutics 15, 3097-3109.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, SynergyFinder™ and SynergyScreen™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

 

NTRC’s key TTK kinase inhibitor patent granted in US

Oss, September, 19th , 2017 – NTRC, a biopharmaceutical company focused on the discovery and development of innovative precision medicines for the treatment of cancer, today announced that the United States Patent and Trademarks Office (USPTO) has granted patent protection for a key patent for its TTK kinase inhibitor programme.

The spindle assembly checkpoint TTK, also known as Mps1, is a key regulator of chromosome segregation and a promising new drug target for the treatment of cancer. Scientists at NTRC, based in Oss, The Netherlands, designed and optimized the novel TTK inhibitors, which exhibit high biochemical and cellular potency. The TTK inhibitors are based on a (5,6-dihydro)pyrimido[4,5-e]indolizine scaffold. This is a completely novel class of synthetic chemical molecules, which are described for the first time in the NTRC patent (WO 2015/155042 A1). The NTRC TTK inhibitors demonstrate very potent anti-proliferative activity in cell-based assays, in the same range as classic cytotoxic agents, but show preference for tumour cells with activated Wnt signalling. In several in vivo cancer models, lead compounds from the series have shown strong reduction of tumour growth or even tumour regression, without toxicity.

Efficacy study NTRC 1501-0, a lead compound from the NTRC TTK inhibitor series, in a xenograft model of the human A427 lung cancer cell line. A427 is mutant for the CTNNB1 gene, coding the Wnt pathway regulator β-catenin. As disclosed by NTRC scientists in another patent application (WO 2016/166255 A1) and in a recent article in Molecular Cancer Therapeutics, tumour cells with activating mutations in the CTNNB1 oncogene show increased sensitivity for TTK inhibitors. In the A427 xenograft model, treatment with NTRC 1501-0 at a dose of 3.75 mg/kg bi-daily, results in tumour regression.

Publications on NTRC’s TTK inhibitor series:

NTRC patents on TTK:

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact info@ntrc.nl

Meet NTRC at Discovery on Target conference in Boston 25 – 29 September, 2017

Oss, September, 19th , 2017 – At the 15th Annual Discovery on Target (DOT) conference to be held in Boston (USA) on 25 – 29 September, Dr. Guido Zaman will present on NTRC’s TTK drug discovery program and its ResidenceTimer™ platform.

Title: Targeted residence time-guided optimization of TTK inhibitors

Kinase Inhibitor symposium, Thursday September 28th, 9:05 – 9:35 a.m.

The interactive breakout discussion on the topic of: New kinase inhibitor targets in cancer immunotherapy will be chaired by Dr. Zaman.

Kinase Inhibitor symposium, Thursday September 28th, 8 to 9 a.m.

NTRC’s high-througput SynergyScreen™ platform for identification of novel synergistic drug combinations will be presented during the poster session by Dr. Suzanne van Gerwen.

Title: Novel synergistic drug combinations of PARP, bromodomain and TTK inhibitors by large scale screen of 150 anti-cancer agents

Exhibition area, Wednesday September 27th p.m. and Thursday September 28th a.m. and p.m.

About NTRC

NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact info@ntrc.nl