Oncology Dose Selection in Subsequent Indications: What Can We Learn From FDA-approved Oncology Drugs?

Purpose: The modern oncology drug development landscape has shifted away from traditional cytotoxic chemotherapies. Following their initial approvals, many oncology drugs have been approved in subsequent indications either as monotherapy or in combination to benefit a broader patient population. To date, dose selection strategies for subsequent indications have not been systematically reviewed.

A Comparative Clinical Pharmacology Analysis of FDA-Approved Targeted Covalent Inhibitors vs. Reversible Inhibitors in Oncology.

Targeted covalent inhibitors (TCIs) are an emerging class of anticancer therapeutics. TCIs are designed to selectively engage their targeted proteins via covalent warheads. From the drug development standpoint, the covalent inhibition mechanism is anticipated to elicit the following theoretical benefits: (i) an extended duration of therapeutic action that is determined by the target protein turnover rate and not necessarily by drug half-life, (ii) a lower therapeutic dose owing to greater pharmacological potency, (iii) lower risk of off-target binding and associated adverse events, and (iv) reduced drug-drug interaction (DDI) liability due to high selectivity and low dose.

Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis.

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes.

Blocking insulin-like growth factor 1 receptor signaling pathway inhibits neuromuscular junction regeneration after botulinum toxin-A treatment.

Botulinum toxin-A (BTX) administration into muscle is an established treatment for conditions with excessive muscle contraction. However, botulinum therapy has short-term effectiveness, and high-dose injection of BTX could induce neutralizing antibodies against BTX. Therefore, prolonging its effects could be beneficial in a clinical situation.

A Narrative Review of u-HA/PLLA, a Bioactive Resorbable Reconstruction Material: Applications in Oral and Maxillofacial Surgery.

The advent of bioresorbable materials to overcome limitations and replace traditional bone-reconstruction titanium-plate systems for bone fixation, thus achieving greater efficiency and safety in medical and dental applications, has ushered in a new era in biomaterial development. Because of its bioactive osteoconductive ability and biocompatibility, the forged composite of uncalcined/unsintered hydroxyapatite and poly L-lactic acid (u-HA/PLLA) has attracted considerable interest from researchers in bone tissue engineering, as well as from clinicians, particularly for applications in maxillofacial reconstructive surgery. Thus, various in vitro studies, in vivo studies, and clinical trials have been conducted to investigate the feasibility and weaknesses of this biomaterial in oral and maxillofacial surgery.

The Epithelial-Mesenchymal Transition Influences the Resistance of Oral Squamous Cell Carcinoma to Monoclonal Antibodies via Its Effect on Energy Homeostasis and the Tumor Microenvironment.

Oral squamous cell carcinoma (OSCC) is a major type of cancer that accounts for over 90% of all oral cancer cases. Recently developed evidence-based therapeutic regimens for OSCC based on monoclonal antibodies (mAbs), such as cetuximab, pembrolizumab, and nivolumab, have attracted considerable attention worldwide due to their high specificity, low toxicity, and low rates of intolerance. However, the efficacy of those three mAbs remains poor because of the low rate of responders and acquired resistance within a short period of time.

Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition.

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy drug resistance. EMT-activating transcription factors (EMT-ATFs), such as Snail, TWIST, and ZEB, can activate several different molecular pathways, e.

Bioactive Regeneration Potential of the Newly Developed Uncalcined/Unsintered Hydroxyapatite and Poly-l-Lactide-Co-Glycolide Biomaterial in Maxillofacial Reconstructive Surgery: An In Vivo Preliminary Study.

Uncalcined/unsintered hydroxyapatite (HA) and poly-l-lactide-co-glycolide (u-HA/PLLA/PGA) are novel bioresorbable bioactive materials with bone regeneration characteristics and have been used to treat mandibular defects in a rat model. However, the bone regenerative interaction with the periosteum, the inflammatory response, and the degradation of this material have not been examined. In this study, we used a rat mandible model to compare the above features in u-HA/PLLA/PGA and uncalcined/unsintered HA and poly-l-lactic acid (u-HA/PLLA).

Inhibition of Alginate Synthesis by Ebselen Oxide and Its Analogues.

is a Gram-negative opportunistic pathogen that is frequently found in the airways of cystic fibrosis (CF) patients due to the dehydrated mucus that collapses the underlying cilia and prevents mucociliary clearance. During this life-long chronic infection, cell accumulates mutations that lead to inactivation of the gene that results in the constitutive expression of operon and the production of alginate exopolysaccharide. The viscous alginate polysaccharide further occludes the airways of CF patients and serves as a protective matrix to shield from host immune cells and antibiotic therapy.

Feasibility of Application of the Newly Developed Nano-Biomaterial, β-TCP/PDLLA, in Maxillofacial Reconstructive Surgery: A Pilot Rat Study.

This study was performed to examine the applicability of the newly developed nano-biocomposite, β-tricalcium phosphate (β-TCP)/u-HA/poly-d/l-lactide (PDLLA), to bone defects in the oral and maxillofacial area. This novel nano-biocomposite showed several advantages, including biocompatibility, biodegradability, and osteoconductivity. In addition, its optimal plasticity also allowed its utilization in irregular critical bone defect reconstructive surgery.

Bone Regeneration Capacity of Newly Developed Uncalcined/Unsintered Hydroxyapatite and Poly-l-lactide-co-glycolide Sheet in Maxillofacial Surgery: An In Vivo Study.

Uncalcined/unsintered hydroxyapatite and poly-l-lactide-co-glycolide (u-HA/PLLA/PGA) is a new bioresorbable nanomaterial with superior characteristics compared with current bioresorbable materials, including appropriate mechanical properties, outstanding bioactive/osteoconductive features, and remarkably shorter resorption time. Nevertheless, the bone regeneration characteristics of this nanomaterial have not been evaluated in maxillofacial reconstructive surgery. In this study, we used a rat mandible model to assess the bone regeneration ability of u-HA/PLLA/PGA material, compared with uncalcined/unsintered hydroxyapatite and poly-l-lactide acid (u-HA/PLLA) material, which has demonstrated excellent bone regenerative ability.

The Effects of Prodrug Size and a Carbonyl Linker on l-Type Amino Acid Transporter 1-Targeted Cellular and Brain Uptake.

The l-type amino acid transporter 1 (LAT1, SLC7A5) imports dietary amino acids and amino acid drugs (e. g., l-DOPA) into the brain, and plays a role in cancer metabolism.

Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies.

The human solute carrier 22A (SLC22A) family consists of 23 members, representing one of the largest families in the human SLC superfamily. Despite their pharmacological and physiological importance in the absorption and disposition of a range of solutes, eight SLC22A family members remain classified as orphans. In this study, we used a multifaceted approach to identify ligands of orphan SLC22A15.

Drug Metabolites Potently Inhibit Renal Organic Anion Transporters, OAT1 and OAT3.

Human OAT1 and OAT3 play major roles in renal drug elimination and drug-drug interactions. However, there is little information on the interactions of drug metabolites with transporters. The goal of this study was to characterize the interactions of drug metabolites with OAT1 and OAT3 and compare their potencies of inhibition with those of their corresponding parent drugs.

Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from .

The enhanced intracellular survival (Eis) protein of () is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of , we designed and optimized structurally unique thieno[2,3-]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy.

Interactions of Oral Molecular Excipients with Breast Cancer Resistance Protein, BCRP.

Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC values less than 5 μM using H-cholecystokinin octapeptide (H-CCK8).

N,N'-diaryl-bishydrazones in a biphenyl platform: Broad spectrum antifungal agents.

N,N'-Diaryl-bishydrazones of [1,1'-biphenyl]-3,4'-dicarboxaldehyde, [1,1'-biphenyl]-4,4'-dicarboxaldehyde, and 4,4'-bisacetyl-1,1-biphenyl exhibited excellent antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N'-diaryl-bishydrazones displayed no antibacterial activity in contrast to previously reported N,N'-diamidino-bishydrazones and N-amidino-N'-aryl-bishydrazones. The leading candidate, 4,4'-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1'-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.

Interfering With DNA Decondensation as a Strategy Against Mycobacteria.

Tuberculosis is once again a major global threat, leading to more than 1 million deaths each year. Treatment options for tuberculosis patients are limited, expensive and characterized by severe side effects, especially in the case of multidrug-resistant forms. Uncovering novel vulnerabilities of the pathogen is crucial to generate new therapeutic strategies.

What are the drugs of the future?

Are small molecules or biologics the drugs of the future? Small-molecule drugs have historically been the pillars of traditional medicine. However, recently, we seem to be amidst a scientific revolution with the rise of many FDA-approved biologic drugs. This opinion article looks at the current state of small molecules and biologics and assesses what the future holds for these two broad classes of drugs.

Potent 1,2,4-Triazino[5,6 b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis.

A common cause of resistance to kanamycin (KAN) in tuberculosis is overexpression of the enhanced intracellular survival (Eis) protein. Eis is an acetyltransferase that multiacetylates KAN and other aminoglycosides, rendering them unable to bind the bacterial ribosome. By high-throughput screening, a series of substituted 1,2,4-triazino[5,6 b]indole-3-thioether molecules were identified as effective Eis inhibitors.

Novel fluconazole derivatives with promising antifungal activity.

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents.

Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents.

The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells.

Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4).

Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity.

Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors.

Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN).

A complex game of hide and seek: the search for new antifungals.

Fungal infections directly affect millions of people each year. In addition to the invasive fungal infections of humans, the plants and animals that comprise our primary food source are also susceptible to diseases caused by these eukaryotic microbes. The need for antifungals, not only for our medical needs, but also for use in agriculture and livestock causes a high demand for novel antimycotics.