Agents In Preclinical Development Research Articles

Pharmacological effects of small molecule BCR-ABL tyrosine kinase inhibitors on platelet function.

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein, such as imatinib (Gleevec), have revolutionized targeted cancer therapies. However, drug resistance and side effects, particularly those affecting hemostasis, continue to pose significant challenges for TKI therapies. As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo Our study included standard-of-care agents (e.g., imatinib and nilotinib), and second-generation ABL inhibitors including ponatinib and bosutinib designed to mitigate drug resistance. Additionally, we explored the effects of allosteric inhibitors targeting the myristoyl pocket of ABL (e.g., asciminib and GNF-2), and novel agents in preclinical development, including ELVN-919, which uniquely exhibits high specificity for the ABL kinase active site. Our findings reveal that while ABL inhibitors such as ponatinib and bosutinib impede platelet activity, highly specific new-generation ABL inhibitors, including first-in-class therapeutics, do not impact platelet function ex vivo Overall, these new insights around the effects of ABL TKIs on platelet function could inform the development of targeted therapies with reduced hematologic toxicities. Significance Statement This study examines the effects of clinically relevant small molecule BCR-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (e.g., imatinib, ponatinib) with well-characterized effects on platelet function, to discern potential anti-platelet and other effects of BCR-ABL TKIs and inform clinical safety.

Granulosa Cells-Related MicroRNAs in Ovarian Diseases: Mechanism, Facts and Perspectives.

MicroRNAs (miRNAs) are a class of short single-stranded, noncoding RNAs that affect the translation of mRNAs by imperfectly binding to homologous 3'UTRs. Research on miRNAs in ovarian diseases is constantly expanding because miRNAs are powerful regulators of gene expression and cellular processes and are promising biomarkers. miRNA mimics, miRNA inhibitors and molecules targeting miRNAs (antimiRs) have shown promise as novel therapeutic agents in preclinical development. Granulosa cells (GCs) are supporting cells for developing oocytes in the ovary. GCs regulate female reproductive health by producing sex hormones and LH receptors. Increasing research has reported the relevance of miRNAs in GC pathophysiology. With in-depth studies of disease mechanisms, there are an increasing number of studies on the biomolecular pathways of miRNAs in gynecology and endocrinology. In the present review, we summarize the different functions of GC-related microRNAs in various ovarian disorders, such as polycystic ovary syndrome, premature ovarian insufficiency, premature ovarian failure and ovarian granulosa cell tumors.

A novel pre-clinical antibacterial pipeline database.

The clinical pipeline continues to be insufficient to contain antimicrobial resistance, and further investment and research is needed to ensure that a robust pipeline is built to treat the WHO priority pathogens list of antibiotic-resistant bacteria. To shed light further upstream on the preclinical pipeline the WHO has undertaken a review of the antibacterial preclinical pipeline and published the data of all identified projects in a publicly accessible database. The database captures 252 unique antibacterial agents in preclinical development being developed by 145 individual institutions, of which the majority are smaller biotech companies and academic institutions. There is a higher degree of innovation in the preclinical pipeline with a significant number of non-traditional approaches being pursued. For even a fraction of these projects to reach clinical development or the market, there is a need to shift the market dynamics for new antibacterials through the identification of new solutions beyond push and pull incentives.

Abstract 1683: A comparative evaluation of immunotherapy responses in murine colon carcinoma

Abstract With the drive in oncology to develop molecules targeting the immune system, there is a need for reliable and well-characterized preclinical models. To this end, the impact of checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1, has been extensively investigated preclinically, and the landscape of available models varies greatly in response to these molecules. With several recent checkpoint inhibitor-based drug approvals, the focus of immuno-oncology drug development has shifted to immunometabolism targets and costimulatory molecules, particularly with combination strategies. Comparative preclinical tumor model validation with respect to these targets is generally lacking; however, the same level of granularity as was afforded anti-PD-1 and anti-PD-L1 would be needed with these molecules to allow confidence in designing preclinical proof of concept studies for future clinical development. To better understand the utility of these agents in preclinical development, we examined the response of two murine colon carcinoma models, CT26 and MC38, against a panel of costimulatory molecules and epacadostat, an IDO inhibitor, using in vivo tumor growth delay studies. Our data demonstrate that CT26 tumors are sensitive to the costimulatory molecules, anti-GITR, anti-CD137, and anti-OX40, resulting in 6/10, 7/10, and 2/10 complete responses (CRs), respectively. In contrast, the response of MC38 tumors to these agents was modest with no CRs and times to evaluation size (TES) extending only 1.4 to 6.9 days beyond control. Epacadostat treatment did not impact growth of CT26 or MC38, with TES's extended by 4.4 or 2.3 days, respectively, compared to control. Interestingly, addition of epacadostat did not improve the response of anti-PD-1 in either model. To determine whether the changes in response could be related to differences in immune infiltration of these tumors, immunophenotyping from untreated CT26 and MC38 tumors was evaluated. We found that immune cell populations also highlighted potential differences in these models. CT26 tumors were well infiltrated with a mean of 25.2% CD45+ cells, with 54.8% of CD3+ cells being CD8+ T cells. Comparatively, MC38 tumors were weakly infiltrated with CD45+ cells (5.3%) with 35.9% of CD3+ cells being CD8+ T cells. Macrophage and MSDC infiltrates, as a percent of CD11b+ cells, in CT26 tumors were generally double that found in MC38 tumors. Our results indicate that CT26 is more sensitive to the costimulatory molecules tested than MC38. Further, epacadostat as monotherapy or in combination with anti-PD-1 did not elicit clinically meaningful tumor growth delay in either model. Stark differences were also seen in overall lymphocyte infiltrate and composition between CT26 and MC38. The differences in baseline immune infiltrate and efficacy allow us to determine which models and immunotherapies are best suited for rational drug combination approaches. Citation Format: Sheri R. Barnes, Sumithra Urs, Mary Anne Meade, David Draper, Hillary Evens, Daniel Saims, Scott Wise, Maryland Rosenfeld Franklin. A comparative evaluation of immunotherapy responses in murine colon carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1683.

Recent advances and current trend in the pharmacotherapy of postmenopausal osteoporosis

Estrogen deficiency (most especially low level of β-estradiol isoform) is the major contributing factor to bone loss after menopause. Supplementation with calcium and Vitamin D is an essential baseline therapy for osteoporosis prevention and treatment. Newer emerging agents that will further expand osteoporosis therapeutic options include strontium compound (a bone selective calcium-sensing receptor [CaSR] agonist or calcimimetic which is currently licensed for use in Europe but not in the US that has both osteoanabolic and antiresorptive activity); Lasofoxifene (a new selective estrogen receptor modulator [SERM] or estrogen agonist-antagonist [EAA] with partial agonist activity at both estrogen receptors ERα and ERβ); odanacatib and balicatib (inhibitors of the resorptive enzyme cathepsin K); abaloparatide (a parathyroid hormone [PTH]-related protein analog); ostabolin-C (a new cyclicised PTH analog); romosozumab and blosozumab (monoclonal antibody inhibitors to sclerostin) which are currently undergoing clinical trial for Food and Drug Administration approval. Other agents in preclinical development include anti-dickkopf antibody (BHQ880) which targets specific protein molecules of the Wnt/β-catenin pathway involved in stimulating new bone formation by osteoblast cells; parathyroid selective short-acting calcium-sensing receptor antagonists or calcilytics (SB-423562, SB-423557, JTT-305/MK-5442, and NPS-2143) that will lead to a transient release of PTH from the parathyroid glands; and saracatinib (a novel orally available competitive inhibitor of the enzyme Src kinase and Abl kinase family shown to inhibit osteoclast-mediated bone resorption). This review article discusses these newer evolving agents that will introduce and incorporate remarkable improvements into the management of postmenopausal osteoporosis in the nearer future.

A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer.

Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. Agents in preclinical development and clinical trials of novel therapeutics targeting HRG-dependent signaling are also discussed, including anti-HER3 and -HER4 antibodies, anti-metalloproteinase agents, and HRG fusion proteins. Although several trials have indicated an acceptable safety profile, translating preclinical findings into clinical practice remains a challenge in this field, possibly due to the complexity of downstream signaling and patterns of HRG, HER3 and HER4 expression in different cancer subtypes. Improving patient selection through biomarkers and understanding the resistance mechanisms may translate into significant clinical benefits in the near future.

Cerebrospinal fluid neurofilament light chain as a biomarker of neurodegeneration in the Tg4510 and MitoPark mouse models

A challenge in working with preclinical models of neurodegeneration has been how to non-invasively monitor disease progression. Neurofilament proteins are established axonal damage markers and have been found to be elevated in cerebrospinal fluid (CSF) and blood from patients with neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies. We hypothesized that CSF neurofilament light (NF-L) can be used to track progression of neurodegeneration and potentially monitor the efficacy of novel therapeutic agents in preclinical development. To substantiate this, we examined whether changes in NF-L levels in brain, plasma, and CSF reflect the changing disease status of preclinical models of neurodegeneration. Using Western Blot and ELISA we characterized NF-L and disease-related proteins in brain, CSF and plasma samples from Tg4510 mice (tauopathy/AD), MitoPark mice (PD), and their age-matched control littermates. We found that CSF NF-L clearly discriminates Tg4510 from control littermates, which was not observed for the MitoPark model. However, both Tg4510 and MitoPark showed altered expression and solubilization of NFs compared to control littermates. We found a significant correlation between CSF NF-L and plasma NF-L in Tg4510, suggesting a similar biomarker potential of plasma NF-L. Also, CSF NF-L correlated significantly with tau in Tg4510 brains, suggesting a surrogate biomarker potential of CSF NF-L. Overall, our findings provide further evidence that NF-L correlates with disease severity and our results suggests, that CSF NF-L has utility as a surrogate or adjunct biomarker for neurodegeneration in the Tg4510 model, but independent validation is warranted.

Tuberculosis: current treatment, diagnostics, and newer antitubercular agents in clinical trials.

Tuberculosis (TB), a dreadful disease is one of the most important health problems worldwide, and is responsible for approximately 1.3 million death tolls in 2012. DOTS is the currently used drug therapy in TB and the long term drug regimens and patients' poor compliance lead to emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB, which invigorates the research efforts to address the urgent need for the quick diagnosis and for newer antitubercular agents and vaccines to completely eradicate TB. Today we have at least 20 new diagnostic test platforms, 14 TB vaccine candidates in clinical trials and over 35 candidates in preclinical development, and among the antitubercular agents under clinical investigation, 4 anti-TB agents are in Phase III (efficacy) trials and 7 anti-TB agents are in Phase II, early bactericidal activity and sputum culture conversion trials (rifapentine is in a Phase II and a Phase III trial), 5 anti-TB agents in preclinical development and 3 anti-TB agents in Good Laboratory Practice toxicity evaluation. Recently US FDA has approved TMC207 as a part of combination therapy to treat adults with MDR pulmonary TB in the absence of other alternatives. We provide here the concise review on the chemical entities currently in the clinical trials, the new vaccines in the developmental pipeline, and the new diagnostic test.

Current and emerging therapies for the treatment of osteoporosis.

Osteoporosis represents a weakening of bone tissue due to an imbalance in the dynamic processes of bone formation and bone resorption that are continually ongoing within bone tissue. Most currently available osteoporosis therapies are antiresorptive agents. Over the past decade, bisphosphonates, notably alendronate and risedronate, have become the dominant agents with newer bisphosphonates such as ibandronate and zoledronic acid following a trend of less frequent dosing regimens. Synthetic estrogen receptor modulators (SERMs) continue to be developed as drugs that maintain the bone-protective effects of estrogen while avoiding its associated adverse side effects. Currently available agents of this class include raloxifene, the only SERM available in the United States (US), and lasofoxifene and bazedoxifene, available in Europe. Calcitonin, usually administered as a nasal spray, completes the list of currently approved antiresorptive agents, while parathyroid hormone analogs represent the only anabolic agents currently approved in both the US and Europe. Strontium ranelate is an additional agent available in Europe but not the US that has both anabolic and antiresorptive activity. New agents expected to further expand therapeutic options include denosumab, a monoclonal antibody inhibitor of the resorptive enzyme cathepsin K, which is in the final stages of Food and Drug Administration approval. Other agents in preclinical development include those targeting specific molecules of the Wnt/β-catenin pathway involved in stimulating bone formation by osteoblast cells. This review discusses the use of currently available agents as well as highlighting emerging agents expected to bring significant changes to the approach to osteoporosis therapy in the near future.

Islet transplantation in patients with diabetes mellitus: choice of immunosuppression.

Islet transplantation offers patients with type 1 diabetes mellitus freedom from long-term insulin therapy and a degree of metabolic control that is far superior to injected insulin. The hope is that near-perfect glucose control sustained over time will prevent progression of secondary diabetic complications. The selection of optimal immunosuppressive agents for islet transplantation has been a formidable challenge, given the need to overcome both autoimmune and alloimmune barriers, as well as the potential toxicity of immunosuppressive agents on transplanted islets. Early strategies relied on protocols that had proven success in solid organ transplantation and consisted of azathioprine, cyclosporine and corticosteroids. Under these protocols, fewer than 10% of patients were able to achieve insulin independence. The development of the 'Edmonton Protocol' dramatically transformed clinical outcomes in islet transplantation in recent years through the introduction of a more potent, less diabetogenic, and corticosteroid-free immunosuppressive regimen consisting of sirolimus, low-dose tacrolimus, and induction anti-interleukin-2 receptor antibody. While insulin independence rates under this protocol have been highly successful, patients must be maintained on lifelong immunosuppression. While the risk of malignancy, post-transplant lymphoma and sepsis have been low and diminishing in transplanted patients to date, fears of these complications and a host of drug-related adverse effects have precluded broader application. Patients undergoing islet transplantation today must exchange insulin for chronic immunosuppressive therapy, and therefore the procedure can only be justified in patients with very unstable forms of diabetes, or in those with another solid organ allograft who already endure the risks of immunosuppression. Advances in more specific and less toxic immunosuppressive agents together with progress in better understanding the biology of diabetes will lead to more suitable strategies to control both alloimmune and recurrent autoimmune reactions. These protocols, ultimately aimed at establishing tolerance, are an essential pre-requisite to move towards providing islet transplantation earlier in the course of the disease, including transplantation in children. This review addresses the evolution of immunosuppressive strategies in islet transplantation, and highlights some novel agents in pre-clinical development or in early clinical trials that may offer considerable promise in facilitating the induction of tolerance.

Agents in development for dementia syndromes in Japan. Summary and table.

All drugs appearing in the Adis Profile Summary table have been selected based on information contained in R&D Insight™, a proprietary product of Adis International. As the emphasis of Drugs in R&D is on the clinical potential of new drugs, selection of agents for full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified from R&D Insight™, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

New chemotherapeutic agents for influenza virus infections. Summary and table.

Adis Comment All drugs appearing in the Adis Profile Summary table have been selected based on information contained in R&D Insight'», a proprietary product of Adis International. As the emphasis of Drugs in R&D is on the clinical potential of new drugs, selection of agents for full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified from R&D Insight'», is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

Agents in development for the treatment of hepatitis C. Summary and table.

All drugs appearing in the Adis Profile Summary table have been selected based on information contained in R&D Insight™, a proprietary product of Adis International. As the emphasis of Drugs in R&D is on the clinical potential of new drugs, selection of agents for full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified from R&D Insight™, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

Agents in development for type 2 diabetes.

All drugs appearing in the Adis Profile Summary table have been selected based on information contained in R&D Insight™, a proprietary product of Adis International. As the emphasis of Drugs in R&D is on the clinical potential of new drugs, selection of agents for full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified from R&D Insight™, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

Neuroprotectants in stroke. Summary and table.

Adis Comment All the drugs appearing in the Adis Profile Summary table have been selected based on information contained in R&D InsightTM, a proprietary product of Adis International. As the emphasis of Drugs in R&D is on the clinical potential of new drugs, selection of agents for a full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified from R&D InsightTM, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

Inflammatory bowel disorders. Summary and table.

Adis Comment All the drugs appearing in the Adis Profile Summary table have been selected based on information contained in R&D InsightTM, a proprietary product of Adis International. As the emphasis of Drugs in R&D is on the clinical potential of new drugs, selection of agents for a full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified from R&D InsightTM, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

Transplant rejection. Summary and table.

Adis Comment All the drugs appearing in the Adis Profile Summary table have been selected based on information contained in R&D InsightTM, a proprietary product of Adis International. As the emphasis of Drugs in R&D is on the clinical potential of new drugs, selection of agents for a full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified from R&D InsightTM, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

Antifungals: mechanism of action and resistance, established and novel drugs

Serious fungal infections, caused mostly by opportunistic species, are increasingly common in immunocompromised and other vulnerable patients. The use of antifungal drugs, primarily azoles and polyenes, has increased in parallel. Yet, established agents do not satisfy the medical need completely; azoles are fungistatic and vulnerable to resistance, whereas polyenes cause serious host toxicity. Drugs in clinical development include echinocandins, pneumocandins, and improved azoles. Promising novel agents in preclinical development include several inhibitors of fungal protein, lipid and cell wall syntheses. Recent advances in fungal genomics, combinatorial chemistry, and high-throughput screening may accelerate the antifungal discovery process.