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Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. Hence, ARG inhibition can reverse immunosuppression enhancing antitumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, ARG inhibitor payload (AZD0011-PL). We demonstrate that AZD0011-PL is unable to permeate cells, suggesting that this compound will only inhibit extracellular ARG. In vivo, AZD0011 monotherapy leads to arginine increases, immune cell activation, and tumor growth inhibition in various syngeneic models. Antitumor responses increase when AZD0011 is combined with anti–PD-L1 treatment, correlating with increases in multiple tumor immune cell populations. We demonstrate a novel triple combination of AZD0011, anti–PD-L1, and anti-NKG2A, and combination benefits with type I IFN inducers, including polyI:C and radiotherapy. Our preclinical data demonstrate AZD0011’s ability to reverse tumor immunosuppression and enhance immune stimulation and antitumor responses with diverse combination partners providing potential strategies to increase immuno-oncology therapies clinically.

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Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. Hence, ARG inhibition can reverse immunosuppression enhancing antitumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, ARG inhibitor payload (AZD0011-PL). We demonstrate that AZD0011-PL is unable to permeate cells, suggesting that this compound will only inhibit extracellular ARG. In vivo, AZD0011 monotherapy leads to arginine increases, immune cell activation, and tumor growth inhibition in various syngeneic models. Antitumor responses increase when AZD0011 is combined with anti–PD-L1 treatment, correlating with increases in multiple tumor immune cell populations. We demonstrate a novel triple combination of AZD0011, anti–PD-L1, and anti-NKG2A, and combination benefits with type I IFN inducers, including polyI:C and radiotherapy. Our preclinical data demonstrate AZD0011’s ability to reverse tumor immunosuppression and enhance immune stimulation and antitumor responses with diverse combination partners providing potential strategies to increase immuno-oncology therapies clinically.

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Primers used for targeted gene profiling on selected RAS/MAPK pathway genes either on Fluidigm or by qRT-PCR on Roche Lightcycler 480

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KRAS mutation status of cell lines included in in vitro combination screen

The RAS-regulated RAF–MEK1/2–ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS-mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF-mutant and KRAS-mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF- and KRAS-mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS-mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS-mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS-mutant tumors.

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Supplementary materials and methods

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Cell lines defined as sensitive to AZD0364 from 747 cell panel screen

Response of 747 cell lines to treatment with AZD0364 for 72 hours.

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This industry update covers the period from January 1 through January 31, 2022, and is based on information sourced from company press releases, scientific literature, patents and news websites. January 2022 saw Janssen and Midatech expand their collaboration on bioresorbable polymer microsphere technology for drug delivery. Takeda announced its plans to acquire UK-based Adaptate Biotherapeutics and Gandeeva raised further investment funds to support its drug discovery and development platform focused on the evaluation of protein–drug interactions. Biogen announced that it will sell its stake in a biosimilars joint venture and ABL Bio and Sanofi announced a collaboration around a novel treatment for Parkinson's disease. New regulatory announcements this month included US FDA approvals of a new insomnia treatment for Idorsia and a treatment for atopic dermatitis developed by Pfizer. Insulet gained FDA clearance for a closed-loop insulin pump and Ascendis Pharma followed up its United States approval last year for a once-weekly treatment for growth hormone deficiency with European approval. Pfizer and Ionis announced the discontinuation of the clinical development of a novel cardiovascular drug. In terms of collaborations, Novartis and Alnylam announced they will work together to explore targeted therapies to restore liver function; Scorpion Therapeutics partnered with AstraZeneca to develop novel cancer treatments and Nutriband Inc. and Kindeva Drug Delivery will work together to develop a transdermal fentanyl patch. Collaborations were also announced between Century Therapeutics and Bristol Myers Squibb and Lilly and Entos Pharmaceuticals in the areas of stem cell therapies for cancer treatment and neurology, respectively. A team from the Massachusetts Institute of Technology reported progress in developing oral mRNA treatments and West Pharmaceutical Services published a blog describing the development of a proof-of-principle system for a closed-loop feedback system targeting opioid overdose. A report on the BBC website highlighted the benefits of more sustainable inhalers.

As part of a drug discovery program, 4-pyrazin-2-yl-1H-pyrrole-2-carboxamides were accessed along with a number of bicyclic analogues. Routes to these compounds were largely absent from the scientific literature. The synthesis of a 4-(pyrazin-2-yl)-1H-pyrrole-2-carboxamide and several fused bicyclic analogues all using standard procedures (SNAr, borylation, C–C cross couplings, hydrolysis, amide bond formation, cyclisation, halogenation, and alkylation) from readily available starting materials is reported. The synthetic sequences range from 4–12 steps per final compound, with yields of isolated intermediates ranging from 20 to ∼100%.

The RAS-regulated RAF–MEK1/2–ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS-mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF-mutant and KRAS-mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF- and KRAS-mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS-mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS-mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS-mutant tumors.

This Industry Update covers the period from 1 to 31 January 2019 and is based on information sourced from company press releases, scientific literature, patents and various news websites. Bristol-Myers Squibb (NY, USA) and Celgene (NJ, USA) announced a merger to create one of the largest oncology-focused pharmaceutical businesses. Also, with a focus on oncology, Lilly (IN, USA) announced it is acquiring Loxo Oncology (CT, USA). Alphabet’s life sciences business, Verily (CA, USA), announced it had raised new funds to invest in new business opportunities and acquisitions. Talee Bio (PA, USA) and Agenus (MA, USA) announced that they had won grants to support their work in cystic fibrosis and vaccine development, respectively. Biogen (MA, USA) established two new collaborations aimed at expanding its neuroscience pipeline and Voyager Therapeutics (MA, USA) and Neurocrine Biosciences (CA, USA) agreed a collaboration to develop and commercialize gene therapy treatments also in neuroscience. In digital health, Proteus Digital Health (CA, USA) continued the development of digital pill technology, with the initiation of a study in oncology and Otsuka (Tokyo, Japan) agreed a collaboration with Click Therapeutics (NY, USA) to develop digital therapies to treat major depressive disorder. This month also finally saw the approval of Mylan’s (PA, USA) generic version of GSK’s (Brentford, UK) blockbuster inhaled drug, ADVAIR. Several developments in novel drug delivery methods were reported including the use of microneedles to deliver contraceptives, inhaled delivery of mRNA and a study supporting the use of peptoids to deliver gene therapies into cells. A publication from the Salk Institute (CA, USA) suggested a cellular mechanism might be important in reducing the risk of cancer, and a study by a team at Washington University (MO, USA) supported the possibility of gene therapy to treat neuropathy.

This industry update covers the period from 1 to 31 October 2018 and is based on information sourced from company press releases, scientific literature, patents and various news websites. With the ...

The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in

2,6-Lutidine has been identified as a beneficial additive for the oxidative cleavage of olefins to ketones by NaIO4 in the presence of catalytic RuCl3, improving the yield and shortening the reaction times. In the absence of 2,6-lutidine reactions stalled at the diol intermediate with incomplete conversion to the desired ketones. The reaction protocol described herein also avoids the use of harmful solvents such as CCl4 and DCE and is tolerant of a range of functional groups.

This industry update covers the period from 1 September through 30 September 2017, and is based on information sourced from company press releases, scientific literature, patents and various news websites. The month saw the US FDA approve three new molecular entities, Aliqopa (copanlisib dihydrochloride) (Bayer Healthcare); Solosec (secnidazole) (Symbiomix Therapeutics) and Verzenio (abemaciclib) (Eli Lilly and Co). Intarcia Therapeutics Inc. has its application for approval of a novel drug device combination of exenatide for the treatment of diabetes rejected by FDA but said that it will work to address the concerns and refile the application. The impact of biosimilars in the market is steadily increasing with seven biosimilars approved in the USA and Sandoz hoping to add to this with its announcement that FDA has accepted its Biologics License Application for a biosimilar version of Roche's Rituxan. Circassia announced positive top line results of a respiratory drug, Duaklir (for the treatment of chronic obstructive pulmonary disease) and Sarepta (for its new treatment for Duchenne muscular dystrophy). Axovant Sciences Ltd announced the failure if its drug Intepirdine in the treatment of Alzheimer's, adding to a growing list of drug failures in this area. There were a number of developments in the area of oncology with Bristol-Myers Squibb and Infinity Pharmaceuticals announcing an expansion of their collaboration looking at combination treatments, as well as Eli Lilly and Co's approval for Verzenio. Rani Therapeutics and Intra-Cellular Therapies announced successful funding rounds to support their drug programs. Allergan announced a novel licensing deal for its dry eye drug, Restasis, which it hopes would allow it to stave off patent challenges from several companies looking to develop generic versions of the drug. New research suggests that loss of sense of smell can be linked to an increased risk of developing Parkinson's disease.

There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.

This industry update covers the period from 1 to 31 October 2018 and is based on information sourced from company press releases, scientific literature, patents and various news websites. With the expiry in Europe of AbbVie's (IL, USA) principal patent on Humira this month, the first biosimilar versions of the drug have been launched. AstraZeneca (Cambridge, UK) announced that is has out-licensed two none core drugs to Grunenthal (Aachen, German), while Pfizer (NY, USA) announced the creation of a new company, set up in collaboration with Bain Capital (MA, USA) to exploit Pfizer's clinical and preclinical assets in the neuroscience field. In digital health, 23andMe (CA, USA) announced that the US FDA has authorized marketing of one of its consumer genetic tests, that assesses the genetic factors that affect drug metabolization, hence the safety and efficacy of some drugs. Novartis (Basel, Switzerland) continued to grow its activities in digital health with the creation of the Novartis Biome, an incubator and support program for early-stage companies in this area. Novartis also announced that it has filed applications in the EU and USA for the approval of siponimod, a drug targeting secondary progressive multiple sclerosis and Roche (Basel, Switzerland) gained FDA approval for an antiviral treatment for influenza. Janssen (Beerse, Belgium) announced it had won a label extension for its blood glucose-lowering drug, Invokana®, for the reduction of cardiovascular events in diabetes. Roche presented data at ECTRIMS, a major annual conference on multiple sclerosis (MS), held in Berlin, Germany this month (10–12 October 2018), showing the potential benefits of administering its drug, Ocrevus, earlier in the treatment pathway for MS compared with other standard treatment. At the same event, Celgene (NJ, USA) presented results from a survey that showed MS patients’ concern around brain atrophy and cognitive loss in MS, highlighting that the disease has a neurodegenerative as well as an inflammatory component. Novartis also presented a significant amount of data supporting its marketed drugs as well as its development pipeline in the disease. This month, presentation of data from two studies at the American Academy of Ophthalmology annual meeting (27–30 October 2018, Chicago, IL, USA) further supporting the potential of eye scans in the early detection of Alzheimer's. A paper by a research team at the University of Rochester (NY, USA) demonstrated the feasibility of a new mechanism to transport drugs across the blood–brain barrier, which could help development more effective CNS drugs.

Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chemical probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies.

Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits. Lead compound 23 from this novel ABI series has a SYK IC50 = 0.21 nM in a biochemical assay and inhibits growth of SUDHL-4 cells at a GI50 = 210 nM.

The symptomatic repertoire of cardiac disease is relatively narrow and most conditions will present with one or more of chest pain, dyspnoea, palpitation, syncope, or presyncope. On the other hand, the differential diagnosis of each of these symptoms is broad and includes both cardiac and non-cardiac disorders. Certain features of acute chest pain alter the likelihood of acute coronary syndrome but, in isolation, the history is usually insufficient to rule in or rule out the diagnosis. Intermittent chest pain can be categorized as typical angina, atypical angina, or non-anginal based on three symptom characteristics; this classification has substantial diagnostic value and helps to determine the need for and the most appropriate mode of further investigation. Orthopnoea and paroxysmal nocturnal dyspnoea are more specific for heart failure than other forms of dyspnoea. However, it is not possible to diagnose either acute or chronic heart failure by the history alone. For both angina and chronic heart failure, the European Society of Cardiology recommends objective assessment of symptom severity using the Canadian Cardiovascular Society and New York Heart Association classifications respectively. Definitive diagnosis of palpitation usually requires documentation of the cardiac rhythm during symptoms but a clear description of the symptom may suggest the likely diagnosis and guide the optimal approach to rhythm monitoring. The history is invaluable in differentiating syncope and presyncope from other causes of transient loss of consciousness and dizziness. Beyond this, clinical features such as prodromal symptoms or precipitation of episodes by exposure to pain can help to distinguish cardiac from reflex syncope.

A procedure for the formation of aryl amides through the palladium-catalyzed coupling of nitriles and aryl bromides, via the formation of intermediary silanoate derived imidate species is reported. Optimization was undertaken and examples of the process are described that furnish the products in up to 86% isolated yield.

This Industry Update covers the period 1–31 March 2014 and is based on information sourced from company press releases, scientific literature, patents and various news websites. This month saw some significant commercial activity with Baxter (IL, USA) announcing a split, Corium an initial public offering and Vectura a major acquisition, which both expands its development pipeline and also gives it access to another inhalation device platform. A number of technologies are under development that enable the transfer of drugs across the blood–brain barrier and MedImmune (MD, USA) continued its interest in the area by announcing a new deal with BiOasis (Vancouver, Canada). In another drug-delivery deal, Caisson (TX, USA) announced an expansion of its HEPtune collaboration with Novo Nordisk (Bagsværd, Denmark). Clinical progress was reported by Arrowhead Research Corporation for its RNAi therapeutic for the treatment of chronic hepatitis, which began a Phase IIa study, and Ocular Therapeutix (MA, USA) embarked on its Phase III clinical program to evaluate the safety and efficacy of its dexamethasone formulation. In the regulatory arena, the US FDA approved oral treatment from Celegene (NJ, USA) for psoriatic arthritis and Avanir (CA, USA) announced the FDA has accepted its new drug application for a nasally delivered sumatriptan for the treatment of migraine. A paper in Nature described an 'on-skin' system that can monitor patients, deliver drugs and communicate data. A paper published by a group form University of Illinois (IL, USA) described a biodegradable battery that could be used to power implanted devices used to deliver drugs.

We report a two step one-pot method for the synthesis of 2-bromo-6-aryl[5 H ]pyrrolo[2,3- b ]pyrazines. The process makes use of a cleaner copper-free Sonogashira coupling and an improved base-mediated 5- exo -dig cyclisation to afford the products in good yields. This method expands the scope to structures that are poorly represented in the literature and incorporates a halide for further synthetic elaboration.

The expedient synthesis of compounds enriched in sp