bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hsp90 Inhibitors
Authors: Blagg Brian S.J. , Hadden Matthew Kyle , Tarpley Reid S. 
Published: April 2021

Abstract
As of 2018, 18 Hsp90 inhibitors have entered clinical trials had been launched toward the treatment of human cancers. The 90 kDa heat shock proteins (Hsp90) are molecular chaperones required for the conformational maturation of a number of key signaling proteins that are often overexpressed and/or mutated in transformed cells. Consequently, small molecule inhibitors of Hsp90 exert a combinatorial attack on cancer cells that may be comparable to the administration of multiple chemotherapeutic agents.
US FDA‐Approved Small‐Molecule Kinase Inhibitors for Cancer Therapy
Authors: Yu Mingfeng , Tadesse Solomon , Wang Shudong 
Published: April 2021

Abstract
Abnormal activation of kinases is associated with various types of human cancer. A milestone approval of a small‐molecule kinase inhibitor (SMKI), imatinib, in 2001 for the treatment of chronic myeloid leukemia has revolutionized the clinical practice. This has invigorated the kinase‐targeted drug discovery and clinical sciences, and drug developers have been searching for the next revolutionary therapeutic agents to combat cancer. By mid‐2019, a total of 48 SMKIs have received their regulatory approvals from the United States Food and Drug Administration (USFDA) for the treatment of cancer. This article starts with an introduction of kinases; emphasis is placed on the differences between the structures of active and inactive kinases in that these structural disparities form the basis of the current classification of SMKIs which is subsequently outlined. Thereafter USFDA‐approved SMKI oncology drugs are delineated, with a great deal of attention paid to their respective oncology indications and co‐crystal structures with indication‐related kinases; an overview of biomedical rationales of the kinases being targeted is also provided. Towards the end, some of the current challenges and future prospects in developing SMKI‐based cancer therapies are discussed.
Cancer Drug Resistance – Targets and Therapies
Authors: Zdrazil Barbara , Ecker Gerhard F. 
Published: April 2021

Abstract
The development of drug resistance represents a major obstacle in tumor therapy. Besides targeted resistance to distinct compounds, multiple drug resistance caused by drug efflux pumps also renders tumor therapy ineffective. In this article, we provide an overview on the main mechanisms of drug resistance in tumor therapy as well as concepts to overcome them.
2010 to 2020: Ten Years of Malaria Drug Discovery
Authors: Yeung Bryan K.S. , Calderón Félix 
Published: April 2021

Abstract
The seventh edition of Burger's Medicinal Chemistry, Drug Discovery and Development included an extensive review of antimalarial drugs and drug targets. Since it was published nearly 10 years ago, the annual number of deaths due to malaria in endemic countries have steadily declined. However, over the past two years, a stabilization in number of malaria deaths hints to a reversal of this trend. This may be in part due to parasite evolution to overcome efficacy of antimalarial therapies, including the now well‐established spread of resistance to artemisinin‐combination therapies in Southeast Asia. Fortunately, the last decade also witnessed a renewed effort by academic researchers, product development partnerships, and pharmaceutical companies to restart malaria drug discovery. Innovations in high‐throughput screening, assay development, access to large chemical libraries, advancements in parasite biology, and whole‐genome sequencing have resulted in the discovery of new antimalarial drugs as well as novel targets. These new drug candidates, which kill the parasite through new mechanisms of action have bolstered the malaria drug development pipeline since the last edition. This article summarizes the new drug discovery approaches and achievements over the past decade.
Cognition
Authors: Young Richard 
Published: April 2021

AbstractCognition can be defined as neurocognitive processes of how humans learn and remember. As humans age, threats of neurocognitive disturbances are probably the most feared psychiatric problems, but these processes also can be disrupted by biological abnormalities closely connected to other psychiatric problems. The theme of this article is that basic research in areas of cognition and advances in the discovery of novel pharmacotherapy for neurocognitive and psychiatric disorders that affect the elderly are inextricably intertwined. Drug evaluations in animal models should be conducted in, three basic types of learning/memory paradigms (habituation, classical conditioning, and operant conditioning) and should assess the effects of agent on learning, retention, and retrieval. The importance of this strategy involves issues of single or multiple learning processes in the paradigms, whether different types of paradigms give rise to different kinds of memories or whether the same paradigm may produce several fundamentally different types of memories that may or may not be interdependent. Medications currently in use for ameliorating neurocognitive disorders are mostly ineffective. New pharmacotherapy is urgently needed, and a seemingly innumerable collection of drugs has been proposed as the latest “key” to unlock mechanisms of dysfunction in neurocognition. In some cases, new agents have functioned (biochemically) exactly as advertised, but virtually all have proved unacceptable for clinically use. Future therapies for neurocognitive disorders will likely benefit from the recognition that multiple cellular mechanisms and neurotransmitter processes are involved and that administration of combinations of agents that provide “wide‐spectrum” actions may be most useful.
Opioid Receptor Ligands
Authors: McCurdy Christopher R. , Prisinzano Thomas E. 
Published: April 2021

AbstractOpioid agonists, exemplified by morphine, have been the most prescribed class of drugs for the management of moderate to severe pain for many years. These drugs have significant liabilities of addiction and constipation over long‐term use and acute overdoses can result in respiratory depression. For over thousands of years, opium and opium‐derived drugs have nonetheless been utilized for their therapeutic and recreational benefits. Due to their liabilities, medicinal chemists and clinicians have worked for years to discover novel agents or treatment courses that would be devoid of these side effects. Still to this day, there are no agents that meet these criteria. Therefore, efforts continue vigorously in the quest for drugs with potent analgesic effects without abuse or side‐effect potential. Many chemical classes have been sought after in this quest and the range from peptides to synthetic compounds to natural products. Morphine offered a template that was rigid and able to provide an enormous amount of structure–function relationships that many of the market analgesics are based on. To complicate matters, the endogenous opioid system is comprised of four distinct receptor subtypes. These receptors are all members of the G‐protein superfamily and are designated as mu (μ, MOP), delta (δ, DOP), kappa (κ, KOP), and nociception (ORL1, NOP). It has been realized over the years that a combination of activities at these receptors may result in agents that could be devoid of liabilities. Intensive efforts have been directed at improved probes for each receptor subtype and combinations of agonists and antagonists for combinations of these receptors. This review will discuss the structure–activity relationships, as they are currently understood, with regard to each of the major classes of compounds that interact with these protein targets.
PET and SPECT in Drug Development
Authors: Welch Andy , Tavares Adriana A. S. , Pimlott Sally , Sutherland Andrew 
Published: April 2021

Abstract
Positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) are noninvasive molecular imaging techniques that can be used to provide functional information in the living human body. They use radiolabeled compounds that bind to specific sites on a biological target, known as radiotracers, enabling us to visualize and characterize specific aspects of a biological process. This article describes these techniques and how they can be utilized in the drug development process.
Cryo‐Electron Microscopy in Drug Discovery and Development: Opportunities and Challenges
Authors: Gomez‐Llorente Yacob , Hong Chuan , Scapin Giovanna 
Published: April 2021

AbstractWhile utilization of structural information has been a staple technology in drug discovery for many years, electron microscopy creates opportunities that have been thus far out of reach for the conventional techniques, like the visualization of very large molecular complexes in solution or obtaining high‐resolution structural data for small molecules from microcrystals. These opportunities come at a cost: hardware is extremely expensive, software is ever‐changing, and constantly challenged by new developments in the hardware and requests by the users, and IT departments are faced with significant requirements for storage and computational power. Nevertheless, the establishment of centralized facilities, commercial consortia, and cooperative research centers is well positioned to provide access to Cryo‐EM to an expanded base of researchers, from academia as well as from industry. Understanding of the requirements, advantages, and limitations of this technique becomes then necessary to ensure correct decision‐making processes and resource allocation when undertaking a structure‐guided drug design project.
Angiogenesis Inhibitors
Authors: Shi Lei 
Published: April 2021

AbstractAngiogenesis, the formation of new capillary blood vessels from preexisting vasculature, plays an essential role in organ growth and wound repair. However, pathological angiogenesis is a hallmark of various cancers and a range of nonneoplastic diseases including ischaemic and inflammatory disorders. Angiogenesis is a complicated multistep process that precisely mediated by the balance between pro‐ and antiangiogenic factors. Concentrated efforts in this area of research have led to the discovery of a growing number of angiogenesis‐related molecules and the complex interactions among these molecules. The integrated understanding of molecular mechanism of angiogenesis process involved in tumor growth and metastasis has identified angiogenesis as a promising target for cancer therapy. Over the past two decades, dozens of antiangiogenic drugs have been approved for the treatment of a variety of cancers. So far, hundreds of thousands of cancer patients have benefited from antiangiogenesis treatments but limited efficacy and resistance remain outstanding problems.This article will focus on tumor angiogenesis‐related signaling molecules and pathways, development of antiangiogenic agents for the treatment of various tumors, and challenge of antiangiogenic therapy of tumors.
Immuno‐Oncology
Authors: Buesking Andrew W. , Mayes Patrick A. , Combs Andrew P. 
Published: April 2021

AbstractThe ability to avoid immune surveillance and destruction is one of the hallmarks of cancer. Identification of ligands that can prevent immune cells from killing malignant cells was the pivotal discovery for which the 2018 Nobel Prize in Medicine was awarded and initiated the current era in cancer immunotherapy. As a result, a number of antibody‐based approaches including checkpoint inhibitors and bispecific antibodies have been explored. More recently, small molecule drugs have emerged as a complementary approach. Small molecules can offer unique advantages over antibody therapies including access to intracellular targets, opportunities for oral dosing, higher relative exposures in the brain, and increased penetration into tumors. This article provides a brief overview of antibody approaches and then summarizes nine immuno‐oncology targets for which small molecule modulators have been described in the peer‐review literature.
Therapeutic Approaches for Nonalcoholic Steatohepatitis (NASH)
Authors: Glatthar Ralf , Arch Robert H. 
Published: April 2021

AbstractNonalcoholic fatty liver disease (NAFLD), the most prevalent liver disease worldwide, is the hepatic manifestation of metabolic syndrome, which often also includes obesity, type 2 diabetes, and dyslipidemia. While NAFLD was thought to be nonprogressive, it has been shown in several studies that 12–40% of NAFLD patients develop its progressive form nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma. There are presently no approved pharmacological agents for the treatment of NAFLD and NASH, but numerous agents are currently being investigated in clinical trials. These innovative therapies include three main approaches: inhibiting or reducing hepatic fat accumulation; ameliorating oxidative stress, inflammation, and apoptosis; and improving hepatic fibrosis by inhibition of fibrogenesis or promoting fibrolysis. This article provides a brief introduction to the underlying disease features and describes the medicinal chemistry and current status of the main low‐molecular‐weight pharmacological agents currently in development for NASH.
Molecular Genetics of Hyperaldosteronism
Authors: Scholl Ute I 
Published: April 2021

Abstract

Primary aldosteronism features excessive production of the adrenal steroid hormone aldosterone, which causes hypertension. Common causes are aldosterone‐producing adenomas (benign tumours) and bilateral hyperaldosteronism. Almost all aldosterone‐producing adenomas carry somatic mutations in known disease genes, including
KCNJ5
(a potassium channel),
CACNA1D
and
CACNA1H
(calcium channels),
ATP1A1
and
AT2B3
(ATPase subunits) and
CLCN2
(a chloride channel). These mutations directly or indirectly cause increased intracellular calcium, elevated aldosterone production and proliferation. Mutations in
CTNNB1
(β‐catenin) are less understood. Bilateral hyperaldosteronism appears to be due to somatic mutations in the so‐called aldosterone‐producing cell clusters, with
CACNA1D
and
ATP1A1
as frequently mutated genes. Familial hyperaldosteronism (FH) is rare. FH‐I, ‐II, ‐III and ‐IV are caused by germline mutations in
CYP11B2
(aldosterone synthase),
CLCN2
,
KCNJ5
and
CACNA1H
, respectively, and a syndrome that includes neurologic abnormalities is due to germline mutations in
CACNA1D
. These observations suggest pathways for the development of novel diagnostic and therapeutic strategies.

Key Concepts

Primary aldosteronism is the most common cause of secondary hypertension, caused by aldosterone‐producing adenomas or bilateral adrenal hyperplasia.

Genetic studies have demonstrated that primary aldosteronism is largely genetic in aetiology.

Somatic mutations in the potassium channel
KCNJ5
explain about 40% of aldosterone‐producing adenomas.

Mutations in
KCNJ5
are associated with female gender, early onset and larger tumour size.

Other somatic mutations in aldosterone‐producing adenomas affect the
CACNA1D
,
ATP1A1
,
ATP2B3
,
CLCN2
,
CACNA1H
and
CTNNB1
genes.

The shared common final pathway of somatic mutations in aldosterone‐producing adenomas is increased calcium signalling, which causes excessive aldosterone production and proliferation.

Bilateral hyperaldosteronism appears to be due to the so‐called aldosterone‐producing cell clusters, which carry somatic mutations in genes implicated in aldosterone‐producing adenomas.

Rare forms of familial hyperaldosteronism (FH) include FH‐I, ‐II, ‐III and ‐IV, caused by germline mutations in
CYP11B2
,
CLCN2
,
KCNJ5
and
CACNA1H
, respectively. PASNA syndrome (primary aldosteronism, seizures and neurologic abnormalities) is due to
de novo
germline mutations in
CACNA1D
.

The identification of the molecular mechanisms of primary aldosteronism suggests pathways for the development of novel diagnostic and therapeutic strategies.
Organic Synaptic Transistors: The Evolutionary Path from Memory Cells to the Application of Artificial Neural Networks
Authors: Shao Lin , Zhao Yan , Liu Yunqi 
Published: April 2021

AbstractThe progress of neural synaptic devices is experiencing an era of explosive growth. Given that the traditional storage system has yet to overcome the von Neumann bottleneck, it is critical to develop hardware with bioinspired information processing functions and lower power consumption. Transistors based on 2D materials, metal oxides, and organic materials have been adopted to mimic the synapse of a human brain, due to their high plasticity, parallel computing, integrated storage, and system information processing. Among these materials used to build transistors, organic semiconductors are considered to be the most promising candidate for neural synaptic devices and bio‐electronics, owing to their easy processing, mechanical flexibility, low cost, good bio‐compatibility, and ductility. This review focuses on the recent advances in organic synaptic devices with various structures, materials, and working mechanisms. The applications of artificial neural networks that integrate multiple organic synaptic transistors are also concretely discussed. Finally, the challenges that organic synaptic devices currently face are discussed and future developments are forecast.
Ultrahigh Sensitive Wearable Pressure Sensors Based on Reduced Graphene Oxide/Polypyrrole Foam for Sign Language Translation
Authors: Zou Xuejing , Chai Yuqiao , Ma Hui , Jiang Qianqian , Zhang Wei , Ma Xinlei , Wang Xusheng , Lian Huiqin , Huang Xueli , Ji Junhui , Xue Mianqi 
Published: April 2021

AbstractPressure sensors have attracted worldwide attention due to their extensive application requirements in wearable devices, flexible touch display, soft robotics, and health monitoring. Although many pressure sensors have been developed, it still remains a grand challenge to achieve ultrahigh sensitivity with good stability in low‐pressure regions. Herein, the polypyrrole (PPy) is introduced to reduced graphene oxide foam (rGOF) via in situ solventless polymerization to manufacture rGO/PPyF, which significantly enhances the sensitivity and stability of the derived sensors. The as‐fabricated sensor demonstrates an ultrahigh sensitivity of 32.32 kPa−1 in the pressure region of 0–21 Pa, high resolution, and excellent cycling stability. Furthermore, the pressure sensor can transform different hand gestures to distinguishable electrical signals in sign language translation, which indicates that the pressure sensor has a bright application prospect in wearable devices and human–computer interaction.
Assessment of fixed‐duration therapies for treatment‐naïve Waldenström macroglobulinemia
Authors: Abeykoon Jithma P. , Zanwar Saurabh , Ansell Stephen M. , Muchtar Eli , He Rong , Greipp Patricia T. , King Rebecca L. , Ailawadhi Sikander , Paludo Jonas , Larsen Jeremy T. , Habermann Thomas M. , Inwards David , Go Ronald S. , Thanarajasingam Gita , Buadi Francis , Dispenzieri Angela , Thompson Carrie A. , Witzig Thomas E. , Lacy Martha , Gonsalves Wilson , Nowakowski Grzegorz S. , Dingli David , Rajkumar Sundararajan Vincent , Kyle Robert A. , Sher Taimur , Roy Vivek , Rosenthal Allison , Chanan‐Khan Asher A. , Reeder Craig , Gertz Morie A. , Kumar Shaji , Kapoor Prashant 
Published: April 2021

AbstractComparative data guiding initial therapy for Waldenström macroglobulinemia (WM), an infrequently encountered non‐Hodgkin lymphoma, are sparse. We evaluated three commonly used rituximab‐based frontline regimens: rituximab‐bendamustine (R‐Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment‐naïve patients with WM, seen at Mayo Clinic between November 1, 2000 and October 31, 2019. The median follow‐up was 4.5 (95%CI: 4–5) years. The R‐Benda cohort (n = 83) demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n = 92, ORR: 78%) or BDR (n = 45, ORR: 84%) cohorts, p = 0.003. Similarly, longer progression‐free survival (PFS) was evident with R‐Benda use [median 5.2 vs. 4.3 (DRC) and 1.8 years (BDR), p < 0.001]. The time‐to‐next therapy (TTNT) favored R‐Benda [median, not‐reached, 4.4 (DRC) and 2.6 years (BDR), p < 0.001). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p = 0.77. In a subset analysis of 142 patients genotyped for MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the patients' MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R‐Benda are superior compared to DRC or BDR in treatment‐naïve patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status.
Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2
Authors: Du Guangyan , Jiang Jie , Wu Qibiao , Henning Nathaniel J. , Donovan Katherine A. , Yue Hong , Che Jianwei , Lu Wenchao , Fischer Eric S. , Bardeesy Nabeel , Zhang Tinghu , Gray Nathanael S. 
Published: April 2021

AbstractAberrant activation of FGFR signaling occurs in many cancers, and ATP‐competitive FGFR inhibitors have received regulatory approval. Despite demonstrating clinical efficacy, these inhibitors exhibit dose‐limiting toxicity, potentially due to a lack of selectivity amongst the FGFR family and are poorly tolerated. Here, we report the discovery and characterization of DGY‐09‐192, a bivalent degrader that couples the pan‐FGFR inhibitor BGJ398 to a CRL2VHL E3 ligase recruiting ligand, which preferentially induces FGFR1&2 degradation while largely sparing FGFR3&4. DGY‐09‐192 exhibited two‐digit nanomolar DC50s for both wildtype FGFR2 and several FGFR2‐fusions, resulting in degradation‐dependent antiproliferative activity in representative gastric cancer and cholangiocarcinoma cells. Importantly, DGY‐09‐192 induced degradation of a clinically relevant FGFR2 fusion protein in a xenograft model. Taken together, we demonstrate that DGY‐09‐192 has potential as a prototype FGFR degrader.
Electrolyte Structure of Lithium Polysulfides with Anti‐Reductive Solvent Shells for Practical Lithium–Sulfur Batteries
Authors: Zhang Xue‐Qiang , Jin Qi , Nan Yi‐Ling , Hou Li‐Peng , Li Bo‐Quan , Chen Xiang , Jin Zhe‐Hui , Zhang Xi‐Tian , Huang Jia‐Qi , Zhang Qiang 
Published: April 2021

AbstractThe lithium–sulfur (Li–S) battery is regarded as a promising secondary battery. However, constant parasitic reactions between the Li anode and soluble polysulfide (PS) intermediates significantly deteriorate the working Li anode. The rational design to inhibit the parasitic reactions is plagued by the inability to understand and regulate the electrolyte structure of PSs. Herein, the electrolyte structure of PSs with anti‐reductive solvent shells was unveiled by molecular dynamics simulations and nuclear magnetic resonance. The reduction resistance of the solvent shell is proven to be a key reason for the decreased reactivity of PSs towards Li. With isopropyl ether (DIPE) as a cosolvent, DIPE molecules tend to distribute in the outer solvent shell due to poor solvating power. Furthermore, DIPE is more stable than conventional ether solvents against Li metal. The reactivity of PSs is suppressed by encapsulating PSs into anti‐reductive solvent shells. Consequently, the cycling performance of working Li–S batteries was significantly improved and a pouch cell of 300 Wh kg−1 was demonstrated. The fundamental understanding in this work provides an unprecedented ground to understand the electrolyte structure of PSs and the rational electrolyte design in Li–S batteries.