A Comprehensive Review of Various Therapeutic Strategies for the Management of Skin Cancer.

Skin cancer (SC) poses a global threat to the healthcare system and is expected to increase significantly over the next two decades if not diagnosed at an early stage. Early diagnosis is crucial for successful treatment, as the disease becomes more challenging to cure as it progresses. However, identifying new drugs, achieving clinical success, and overcoming drug resistance remain significant challenges. To overcome these obstacles and provide effective treatment, it is crucial to understand the causes of skin cancer, how cells grow and divide, factors that affect cell growth, and how drug resistance occurs. In this review, we have explained various therapeutic approaches for SC treatment via ligands, targeted photosensitizers, natural and synthetic drugs for the treatment of SC, an epigenetic approach for management of melanoma, photodynamic therapy, and targeted therapy for BRAF-mutated melanoma. This article also provides a detailed summary of the various natural drugs that are effective in managing melanoma and reducing the occurrence of skin cancer at early stages and focuses on the current status and future prospects of various therapies available for the management of skin cancer.

Self-Emulsifying Drug Delivery System for Enhanced Oral Delivery of Tenofovir: Formulation, Physicochemical Characterization, and Bioavailability Assessment.

Tenofovir (TNF) is a common component of many antiretroviral therapy regimens, but it is associated with poor membrane permeability and low oral bioavailability. To improve its oral bioavailability and membrane permeability, a self-emulsifying drug delivery system (SEDDS) was developed and characterized, and its relative bioavailability was compared to the marketed tablets (Tenof). Based on solubility and ternary phase diagram analysis, eucalyptus oil was selected as an oil phase, Kolliphor EL, and Kollisolv MCT 70 were chosen as surfactant and cosurfactant, respectively, while glycerol was used as cosolvent in surfactant mixture. Optimized SEDDS formulation F6 showed an oil droplet size of 98.82 nm and zeta potential of -13.03 mV, indicating the high stability of oil droplets. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy characterization studies were also carried out to assess the amorphous and morphological states of the drug in the prepared SEDDS formulation. The in vitro dissolution profile of SEDDS shows the rapid release of the drug. SEDDS F6 demonstrates a higher drug permeability than the plain TNF and TNF-marketed tablets (Tenof). A pharmacokinetic study in rats revealed that SEDDS F6 showed significantly higher Cmax and AUC0-t than the marketed tablets and pure drug suspension. In addition, the relative bioavailability of SEDDS formulation dramatically improved by 21.53-fold compared to marketed tablets and 66.27-fold compared to pure drugs. These findings show that SEDDS composed of eucalyptus oil, glycerol, Kolliphor EL, and Kollisolv MCT 70 could be a useful tool for enhancing physiochemical properties and oral TNF absorption. Therefore, SEDDS has shown promise in improving the oral bioavailability of poorly water-soluble drugs.

Endoscopic classification system of pars tensa retractions.

BACKGROUND: Previous classification systems of pars tensa retractions have not consistently incorporated ossicular erosion or the presence of cholesteatoma. OBJECTIVE: This study aimed to illustrate our classification of pars tensa retractions, which is more precise than previous systems, with aided use of the endoscope. METHODS: A retrospective study was carried out on 200 ears of 170 patients whose pars tensa retractions had been documented at a tertiary otological referral centre. RESULTS: A classification system was developed. Pars tensa retractions were divided into the following subcategories: grade 0, grade 1, grade 2a, grade 2b, grade 3a, grade 3b, grade 3c, grade 4a, grade 4b, grade 4c, grade 5a, grade 5b and grade 5c. CONCLUSION: This classification system was able to accommodate all pars tensa retractions. The distribution of grades of pars tensa retractions was based on ossicular status and the presence or absence of cholesteatoma. It is therefore a more applicable, and functionally based system than previous alternatives.

Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism.

The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and pKa. A systematic optimization of cinacalcet to reduce its cLogP and pKa yielded compound 23a (LNP1892). Compound 23a showed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, 23a demonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with 23a in healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.

Innovative Wound Healing Hydrogel Containing Chicken Feather Keratin and Soy Isoflavone Genistein: In Vivo Studies.

The current study was performed to isolate keratin from chicken feathers with an intention to develop a keratin-genistein wound-healing hydrogel, along with its in vivo analysis. Pre-formulation aspects were analysed by using FTIR; SEM; HPTLC, while gel was characterized for gel strength, viscosity, spreadability, drug content, etc. Additionally, an in vivo study along with biochemical factors against pro-inflammatory factors and histopathological studies were conducted to determine possible wound-healing and anti-inflammatory effects. Pre-formulation studies revealed the presence of amide bonds with region of dense fibrous keratin and an internal porous network in extracted keratin, which corresponds with standard keratin. Evaluation of optimised keratin-genistein hydrogel indicated the development of neutral, non-sticky hydrogel which spread evenly on the skin. In vivo studies in rats indicate higher degrees of wound-healing in combined hydrogel (94.65%) for a duration of 14 days as compared to an individual hydrogel formulation with the development of the epidermis and excessive proliferation of fibrous connective tissue indicating wound repair. Furthermore, the hydrogel inhibited the overexpression of IL-6 gene along with other pro-inflammatory factors, indicating its anti-inflammatory effects. In order to find out the possibility of closure of wounds and anti-inflammatory properties of the novel product, an in vivo investigation into the healing of wounds in laboratory animals was carried out through biochemical (ELISA and qRT-PCR) analyses against inflammatory markers (IL-2, IL-6, IL-1, IL-10, and COX-2) and histopathological (liver, skin, and the kidneys) investigations. Based on the results, we conclude that keratin-genistein hydrogel is a promising therapeutic molecule for the management of wound repair.

Management of attic retraction pockets.

OBJECTIVE: Attic retraction pockets, classified by degree of invasion and erosion, are reconstructed here as outlined by attic retraction pocket grade. METHOD: Attic retraction pocket grade, surgical management, subsequent conditions of tympanic membrane and middle ear, and improvement of air-bone gap pure tone average were recorded. RESULTS: Our management strategy, based on attic retraction pocket grade, was applied to 200 ears: 44 grade I ears had non-surgical management and 156 grade II-V ears had surgical management. All 200 ears were followed up for 36-240 months, showing only 1 attic retraction pocket reformation and 1 adhesive otitis media (complication rate of 1 per cent), and improved air-bone gaps (p < 0.05). An earlier series of 50 grade IV attic retraction pockets used atticotomy with epitympanic reconstruction. These showed attic retraction pocket recurrence or cholesteatoma onset in 34 ears (68 per cent). When these ears were revised per protocol, there was no evidence of cholesteatoma thereafter. CONCLUSION: Reconstruction of the ossicles and scutal defect according to attic retraction pocket grade shows long-term stability of the tympanic membrane, middle ear and hearing.

Development of phospholipon®90H complex nanocarrier with enhanced oral bioavailability and anti-inflammatory potential of genistein.

Genistein (GEN), an isoflavonoid, offers multifunctional biological activities. However, its poor oral bioavailability, aqueous solubility, extensive metabolism, and short half-life restricted its clinical use. Therefore, the Phospholipon®90H complex of genistein (GPLC) was prepared to enhance its biopharmaceutical properties and anti-inflammatory activity. GPLC was characterized by employing particle size and zeta potential, Fourier transforms infrared spectrophotometry, differential scanning calorimetry, powder x-ray diffractometry, proton nuclear magnetic resonance, aqueous solubility, in vitro dissolution, ex vivo permeation, oral bioavailability and in vivo anti-inflammatory activity. The complex showed high entrapment of GEN (∼97.88% w/w) within the Phospholipon®90H matrix. Particle size and zeta potential studies confirmed the small particle size with the modest stability of GPLC. The characterization analysis supported the formation of GPLC through the participation of hydrogen bonding between GEN and Phospholipon®90H. GPLC significantly enhanced the aqueous solubility (∼2-fold) compared to GEN. Dissolution studies revealed that GPLC drastically improved the GEN dissolution rate compared to GEN. Likewise, the complex improved the permeation rate across the membrane compared to GEN. GPLC formulation significantly enhanced the oral bioavailability of GEN via improving its Cmax, tmax, AUC, half-life and mean residence time within the blood circulation compared to GEN. The GPLC (∼20 mg/kg, p.o.) remarkably inhibited the increase in paw edema up to 5 h, compared to GEN and diclofenac. Results suggest that the Phospholipon®90 complex is a superior and promising carrier for enhancing the biopharmaceutical parameters of GEN and other bioactive with similar properties.

Effect of PEGylation on drug uptake, biodistribution, and tissue toxicity of efavirenz-ritonavir loaded PAMAM G4 dendrimers.

The present investigations aimed to compare the efficiency of PAMAM G4 (PG4) and PEGylated PAMAM G4 (PPG4) dendrimers as novel nanocarriers for the treatment of HIV-1. Synthesized PG4 and PPG4 dendrimers were confirmed by electrospray ionization and particle size with its morphology. The anti-human immunodeficiency virus (HIV) drug efavirenz (EFV) with a booster dose of ritonavir (RTV) was encapsulated into PG4 and PPG4 formerly noted as PG4ER and PPG4ER, respectively. Further, evaluated for dendrimers mediated solubilization, drug release, cytotoxicity, drug uptake, plasma, and tissue pharmacokinetics, and histopathology. PG4ER and PPG4ER both promoted a prolonged release of EFV in weakly acidic pH 4 up to 84 h and 132 h, respectively. The results of the cytotoxicity assay and drug uptake study showed that PPG4ER was safe and biocompatible up to 12.5 µg/ml. The plasma pharmacokinetic profile of EFV and RTV was significantly increased by PPG4ER with prolonged t1/2 up to three times as compared to free EFV-RTV and PG4ER. Histopathological analysis showed remarkably lower tissue toxicity in PPG4ER as compared to free EFV-RTV. Therefore, overall data suggested that PPG4 has a great potential for prolonged release of EFV and RTV with enhanced bioavailability and lower toxicity.

Liposomes in the Targeted Gene Therapy of Cancer: A Critical Review.

Cancer immunotherapy has advanced significantly in recent years. Nanocarriers like liposomes can improve cancer immunotherapy and even stronger immune responses by improving cell type-specific distribution. Liposomes are lipid bilayer vesicles that are biodegradable and biocompatible and are often used as smart delivery systems for both hydrophobic and hydrophilic bioactive. Whereas the idea of employing liposomes for administering drugs has been known since the 1960s, the early 2000s saw continuing technological advances and formulations for drug entrapment and manufacturing. Modern deterministic studies have tried discovering more about how genetic material is delivered through liposomes. Liposomes' interactions with cells are still a bit of mystery. Liposome-mediated transmission of genetic material experiences systemic impediments perlysosomal degradation, endosomal escape, and nuclear uptake. Controlling the physical architecture and chemical properties of liposome structures, such as lipid-to-DNA charge, ester bond composition, size, and ligand complexation structure, is critical for targeting liposomes' success as vehicles for gene delivery. This analysis focuses on advancements in ligand-targeted liposomes and theranostic (diagnostic) liposomes for cancer diagnosis and treatment. This review will explore the numerous transgene mechanisms and molecular targets implicated in cancer cell death and the associated benefits of using liposomal formulations throughout the years. This sequence of breakthroughs will interest aspiring researchers and the pharmaceutical industry involved in liposome development.

Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282.

Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.

A Unified Classification of Middle Ear and Petrous Bone Congenital Cholesteatomas.

BACKGROUND: The aim of this study was to classify congenital cholesteatoma along an entire spectrum of involvement ranging from the middle ear to petrous apex. METHODS: A total of 131 patients (85 adults and 46 children) underwent operations for congenital cholesteatoma over the duration of 27 years. RESULTS: For most cases, middle ear mucosa was normal, the first ossicle eroded by the mass was the stapes, and the mastoid air cell system was well-pneumatized on intraoperative and radiographic views. Totally 34% of patients presented with facial nerve weakness and 45% of these cholesteatomas arose from the supralabyrinthine area (32.8%) and from the petrous apex (12.2%). CONCLUSION: In this unified classification system, the otologist sees congenital cholesteatoma as a continuum, with facial nerve involvement and anacusis as part of the picture. This system of congenital cholesteatoma accommodates the supralabyrinthine and petrous bone locations of the disease.

Improvement in Bioavailability and Pharmacokinetic Characteristics of Efavirenz with Booster Dose of Ritonavir in PEGylated PAMAM G4 Dendrimers.

Efavirenz (EFV) with a booster dose of ritonavir (RTV) (EFV-RTV) inhibits the metabolism of EFV and improves its bioavailability. However, inadequate organ perfusion with surface permeability glycoprotein (P-gp) efflux sustains the viable HIV. Hence, the present investigations were aimed to evaluate the pharmacokinetics and tissue distribution efficiency of EFV by encapsulating it into PEGyalated PAMAM (polyamidoamine) G4 dendrimers with a booster dose of RTV (PPG4ER). The entrapment efficiency of PEGylated PAMAM G4 dendrimers was found to be 94% and 92.12% for EFV and RTV respectively with a zeta potential of 0.277 mV. The pharmacokinetics and tissue distribution behavior of EFV within PPG4ER was determined by developing and validating a simple, sensitive, and reliable bioanalytical method of RP-HPLC. The developed bioanalytical method was very sensitive with a quantification limit of 18.5 ng/ml and 139.2 ng/ml for EFV and RTV, respectively. The comparative noncompartmental pharmacokinetic parameters of EFV were determined by administrating a single intraperitoneal dose of EFV, EFV-RTV, and PPG4ER to Wistar rats. The PPG4ER produced prolonged release of EFV with a mean residential time (MRT) of 24 h with Cmax 7.68 µg/ml in plasma against EFV-RTV with MRT 11 h and Cmax 3.633 µg/ml. The PPG4ER was also detected in viral reservoir tissues (lymph node and spleen) for 3-4 days, whereas free EFV and EFV-RTV were cleared within 72 h. The pharmacokinetic data including Cmax, t1/2, AUCtot, and MRT were significantly improved in PPG4ER as compared with single EFV and EFV-RTV. This reveals that the PPG4ER has great potential to target the virus harbors tissues and improve bioavailability.

Discovery and pre-clinical characterization of a selective PI3Kδ inhibitor, LL-00071210 in rheumatoid arthritis.

PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kß as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with ∼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.

The Thickness of the facial Nerve Sheath Consistently Varies by Region in Its Intra-Tympanic Course on Cadaveric Study.

OBJECTIVES: Iatrogenic removal of intra-temporal disease processes, such as cholesteatoma and keratosis obturans, can be challenging when the facial nerve (FN) is involved. Despite this concern about possible FN injury during these procedures, our clinical observation has been that the diseased growth can be cleaned quite easily from the vertical FN epineurium. Therefore, we designed a cadaveric protocol to measure thickness of the FN sheath (epineurium) in horizontal, second genu and vertical FN segments and to correlate these measurements with surgical management of FN disorders. METHODS: Fifty non-fixated (wet) cadaveric temporal bones were dissected over 1 year's time. The intra-temporal FN sheath epineurium was harvested from the mid-horizontal, second genu, and mid-vertical segments. Using a digital micrometric technique, the thickness of each sample was measured. Data analysis was performed using student's two-tailed, dependent t-test. RESULTS: Epineurial nerve sheath thickness was the least in the horizontal segment (mean 0.9 mm, range 0.040-0.140 mm), greater at the second genu (mean 0.19 mm, range 0.010-0.280 mm), and greatest in the vertical segment (mean 0.29 mm, range 0.170-0.570 mm). These differences were statistically significant. CONCLUSION: In cases of cholesteatoma and keratosis obturans involving the vertical FN, the disease process can be separated from the FN sheath because of the sheath thickness in this region. Disease in the horizontal segment involves a thinner sheath and separating the disease process from the nerve is more difficult in this area.

Toxicity and Surface Modification of Dendrimers: A Critical Review.

Compared to other nano polymers, dendrimers have novel three-dimensional, synthetic hyperbranched, nano-polymeric structures. These supramolecular dendritic structures have a high degree of significant surface and core functionality in the transportation of drugs for targeted therapy, specifically in host-guest response, gene transfer therapy, and imaging of biological systems. However, there are conflicting shreds of evidence regarding biological safety and dendrimers toxicity due to their positive charge at the surface. It includes cytotoxicity, hemolytic toxicity, haematological toxicity, immunogenicity, and in vivo toxicity. Surface modification of the dendrimer group is one of the methods to resolve these issues. This review aimed at investigating different strategies that can reduce toxicity and improve the biocompatibility of different dendrimers. From that viewpoint, we broaden the structural and safe characteristics of the dendrimers in the biomedical and pharmaceutical fields.

Unmitigated negative nasopharyngeal pressure is associated with attic retraction pocket formation: LaPlace's law in action.

BACKGROUND: Decades of clinical observation have led our subspecialty team to suspect that negative nasopharyngeal pressure is associated with attic retraction pocket formation. Furthermore, LaPlace's law, which states that the pressure within a sphere varies with the inverse of the radius, provides the dynamic explanation for why the attic area of the tympanic membrane tends to retract more frequently than the pars tensa. METHODS: The attic retraction pockets of 154 patients were classified into grades of severity (grades I-V). Impedance audiometry of middle-ear pressure was measured in the resting state, and after sniffing, swallowing and the Valsalva manoeuvre. RESULTS: Negative nasopharyngeal pressure (sniffing) caused a diminution of middle-ear pressure of -5 daPa on average in normal ears, and of -24 daPa to -45 daPa for tympanic membranes with attic retraction pockets of grade I to grade V. CONCLUSION: Attic retraction pockets are associated with greater collapse of middle-ear volume when negative pressure is created in the nasopharynx. LaPlace's law, and the composition of the pars flaccida, suggests an explanation for why the attic region retracts more than the pars tensa.

An economic model to assess the value of triclosan-coated sutures in reducing the risk of surgical site infection in a mastectomy in India.

BACKGROUND: The comparison of triclosan-coated sutures (TCS) was made with conventional nonantimicrobial-coated sutures (NCS) to reduce surgical site infection (SSI). This study demonstrates the efficacy and economic outcome of TCS versus NCS for SSIs in mastectomy in India. METHODS: In this retrospective analysis, 100 patients were included for both conditions-TCS and NCS-from a private and public hospital in India. A systematic literature search of available evidence for both SSI incidences and TCS efficacy data in India were gathered. We collected cost data from a private and public hospital, respectively, for mastectomy in India. The cost-effectiveness of TCS in comparison with the conventional NCS was calculated using a decision-tree deterministic model. We performed a one-way sensitivity analysis to compare TCS with NCS. RESULTS: Cost savings with the use of TCS increased with an increase in SSI incidence and an increase in efficacy for mastectomies in both public and private hospitals. We found a base cost saving of Indian rupees (INR) 27,299 at a private hospital and INR 2,958 at a public hospital for mastectomies. The incremental cost of TCS suture was 0.01% in a private hospital whereas 0.17% in a public hospital. CONCLUSION: The use of TCS resulted in reduced SSI incidence and cost savings for mastectomy in India.

Potential of luminescent materials in phototherapy.

Phototherapy is the use of light in the treatment of skin diseases that show improvement upon exposure to natural sunlight or man-made lamps. Artificial phototherapy treatments like Narrow band UVB (NB-UVB) phototherapy, Photochemotherapy by UVA (PUVA) and Targeted phototherapy are safe and widely used for several skin diseases like psoriasis, vitiligo, acne vulgaris, mycosis fungoides etc. Photodynamic therapy (PDT), a specialized phototherapy involves use of efficient photo sensitizers and optical radiations for the treatment of cancer and various other medical maladies. Efficacy of these treatments depends on proper selection of a phototherapy lamp which is decided by the wavelength of light emitted by the luminescent material present in it. These luminescent materials on account of their unique luminescence features of portability, power efficiency, lesser heat generation and durability find widespread application in bioassay and therapy. Here, we have discussed about the potential of various luminescent materials for phototherapy on the basis of their photoluminescence behaviour and also tabulated their application for various dermatoses. A few more luminescent materials are discussed in view of current developments in phototherapy and bioscience.

Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.