Toward noncontact macroscopic imaging of multiple cancers using multi-spectral inelastic scattering detection.

Here we introduce a Raman spectroscopy approach combining multi-spectral imaging and a new fluorescence background subtraction technique to image individual Raman peaks in less than 5 seconds over a square field-of-view of 1-centimeter sides with 350 micrometers resolution. First, human data is presented supporting the feasibility of achieving cancer detection with high sensitivity and specificity - in brain, breast, lung, and ovarian/endometrium tissue - using no more than three biochemically interpretable biomarkers associated with the inelastic scattering signal from specific Raman peaks. Second, a proof-of-principle study in biological tissue is presented demonstrating the feasibility of detecting a single Raman band - here the CH2/CH3 deformation bands from proteins and lipids - using a conventional multi-spectral imaging system in combination with the new background removal method. This study paves the way for the development of a new Raman imaging technique that is rapid, label-free, and wide field.

Correlation of in vitro cell viability and cumulative singlet oxygen luminescence from protoporphyrin IX in mitochondria and plasma membrane.

SIGNIFICANCE: Photodynamic therapy (PDT) can be targeted toward different subcellular localizations, and it is proposed that different subcellular targets vary in their sensitivity to photobiological damage. Since singlet oxygen (1O2) has a very short lifetime with a limited diffusion length in cellular environments, measurement of cumulative 1O2 luminescence is the most direct approach to compare the PDT sensitivity of mitochondria and plasma membrane. APPROACH: PDT-generated near-infrared 1O2 luminescence at 1270 nm was measured together with cell viability for 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) and exogenous PpIX, at different incubation times. Confocal fluorescence microscopy indicated that ALA-induced PpIX (2 h) localized in the mitochondria, whereas exogenous PpIX (1 h) mainly localized to the plasma membrane. Cell viability was determined at several time points during PDT treatments using colony-forming assays, and the surviving fraction correlated well with cumulative 1O2 luminescence counts from PpIX in mitochondria and plasmas membrane, respectively. RESULTS: The mitochondria are more sensitive than the plasma membrane by a factor of 1.7. CONCLUSIONS: Direct 1O2 luminescence dosimetry's potential value for comparing the PDT sensitivity of different subcellular organelles was demonstrated. This could be useful for developing subcellular targeted novel photosensitizers to enhance PDT efficiency.

Discovery of Conformationally Constrained ALK2 Inhibitors.

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors M4K2308 and M4K2281 and the amine-linked inhibitors M4K2304 and M4K2306, each with superior potency against ALK2. Notably, M4K2304 and M4K2306 exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG.

Femtosecond pulsed laser photodynamic therapy activates melanin and eradicates malignant melanoma.

Photodynamic therapy (PDT) relies on a series of photophysical and photochemical reactions leading to cell death. While effective for various cancers, PDT has been less successful in treating pigmented melanoma due to high light absorption by melanin. Here, this limitation is addressed by 2-photon excitation of the photosensitizer (2p-PDT) using ~100 fs pulses of near-infrared laser light. A critical role of melanin in enabling rather than hindering 2p-PDT is elucidated using pigmented and non-pigmented murine melanoma clonal cell lines in vitro. The photocytotoxicities were compared between a clinical photosensitizer (Visudyne) and a porphyrin dimer (Oxdime) with ~600-fold higher σ2p value. Unexpectedly, while the 1p-PDT responses are similar in both cell lines, 2p activation is much more effective in killing pigmented than non-pigmented cells, suggesting a dominant role of melanin 2p-PDT. The potential for clinical translational is demonstrated in a conjunctival melanoma model in vivo, where complete eradication of small tumors was achieved. This work elucidates the melanin contribution in multi-photon PDT enabling significant advancement of light-based treatments that have previously been considered unsuitable in pigmented tumors.

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle.

Zinc-finger ubiquitin-binding domains (ZnF-UBDs) are noncatalytic domains mostly found in deubiquitylases (DUBs) such as USP3. They represent an underexplored opportunity for the development of deubiquitylase-targeting chimeras (DUBTACs) to pharmacologically induce the deubiquitylation of target proteins. We previously showed that ZnF-UBDs are ligandable domains. Here, a focused small molecule library screen against a panel of 11 ZnF-UBDs led to the identification of compound 59, a ligand engaging the ZnF-UBD of USP3 with a KD of 14 µM. The compound binds the expected C-terminal ubiquitin binding pocket of USP3 as shown by hydrogen-deuterium exchange mass spectrometry experiments and does not inhibit the cleavage of K48-linked diubiquitin by USP3. As such, this molecule is a chemical starting point toward chemical tools that could be used to interrogate the function of the USP3 Znf-UBD and the consequences of recruiting USP3 to ubiquitylated proteins.

Adaptation of a Clinical High-Frequency Transrectal Ultrasound System for Prostate Photoacoustic Imaging: Implementation and Pre-clinical Demonstration.

OBJECTIVE: High-frequency, high-resolution transrectal micro-ultrasound (micro-US: ≥15 MHz) imaging of the prostate is emerging as a beneficial tool for scoring disease risk and accurately targeting biopsies. Adding photoacoustic (PA) imaging to visualize abnormal vascularization and accumulation of contrast agents in tumors has potential for guiding focal therapies. In this work, we describe a new imaging platform that combines a transrectal micro-US system with transurethral light delivery for PA imaging. METHODS: A clinical transrectal micro-US system was adapted to acquire PA images synchronous to a tunable laser pulse. A transurethral side-firing optical fiber was developed for light delivery. A polyvinyl chloride (PVC)-plastisol phantom was developed and characterized to image PA contrast agents in wall-less channels. After resolution measurement in water, PA imaging was demonstrated in phantom channels with dyes and biodegradable nanoparticle contrast agents called porphysomes. In vivo imaging of a tumor model was performed, with porphysomes administered intravenously. RESULTS: Photoacoustic imaging data were acquired at 5 Hz, and image reconstruction was performed offline. PA image resolution at a 14-mm depth was 74 and 261 µm in the axial and lateral directions, respectively. The speed of sound in PVC-plastisol was 1383 m/s, and the attenuation was 4 dB/mm at 20 MHz. PA signal from porphysomes was spectrally unmixed from blood signals in the tumor, and a signal increase was observed 3 h after porphysome injection. CONCLUSION: A combined transrectal micro-US and PA imaging system was developed and characterized, and in vivo imaging demonstrated. High-resolution PA imaging may provide valuable additional information for diagnostic and therapeutic applications in the prostate.

AAPM Task Group Report 311: Guidance for performance evaluation of fluorescence-guided surgery systems.

The last decade has seen a large growth in fluorescence-guided surgery (FGS) imaging and interventions. With the increasing number of clinical specialties implementing FGS, the range of systems with radically different physical designs, image processing approaches, and performance requirements is expanding. This variety of systems makes it nearly impossible to specify uniform performance goals, yet at the same time, utilization of different devices in new clinical procedures and trials indicates some need for common knowledge bases and a quality assessment paradigm to ensure that effective translation and use occurs. It is feasible to identify key fundamental image quality characteristics and corresponding objective test methods that should be determined such that there are consistent conventions across a variety of FGS devices. This report outlines test methods, tissue simulating phantoms and suggested guidelines, as well as personnel needs and professional knowledge bases that can be established. This report frames the issues with guidance and feedback from related societies and agencies having vested interest in the outcome, coming from an independent scientific group formed from academics and international federal agencies for the establishment of these professional guidelines.

Integrating STEADI for Falls Prevention in Outpatient Rehabilitation Clinics: An Outcomes Evaluation Using the RE-AIM Framework.

BACKGROUND AND OBJECTIVES: The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework was used to describe the implementation of the Stopping Elderly Accidents, Deaths, and Injuries (STEADI) Initiative (2018-2021) for screening and assessing all older adults ≥65 years for falls risk across 34 outpatient rehabilitation clinics within a large health system. RESEARCH DESIGN AND METHODS: We described the Implementation process and strategies. Using Electronic Health Records (EHRs), we identified Reach, Adoption, and Maintenance of screenings and physical assessments to identify fall risk among older adults. RESULTS: STEADI Implementation strategies included health system mandates, EHR revisions, email instructions, educational sessions and resources, clinical leads and champions, and chart audits. Reach: 76.4% (50,023) had a completed screening, and 44.1% screened at risk for falls. Adoption: Clinic-level adoption varied, with most performing screenings. Profession-level adoption was highest for physical therapists (PTs; 94.2% initiated, 80.6% completed) and lowest for speech-language pathologists (SLPs; 79.8% initiated, 55.9% completed). Reach and Adoption of functional outcomes measures (FOM): PTs completed an FOM on 59.5% of at-risk patients, occupational therapists on 11.6%, and SLPs on 7.9%. Maintenance: All measures declined 1%-10% annually between 2018 and 2021. DISCUSSION AND IMPLICATIONS: STEADI screening and FOMs were implemented systemwide in 34 outpatient rehabilitation clinics, reaching over 50,000 older adults. Screening adoption rates varied by clinic. PTs had the highest adoption rate. All adoption rates declined over time. Future research should consider an implementation science approach with input from key partners before implementation to identify barriers and develop strategies to support STEADI in outpatient rehabilitation.

Investigating the effects of a temperature dependent photodynamic dose: A numerical study.

SIGNIFICANCE: Photodynamic therapy (PDT) and photothermal therapy (PTT) show promise as cancer treatments, but challenges in generating large ablative volumes for deep-seated tumours persist. Using simulations, this study investigates combined PDT and PTT to increase treatment volumes, including the impact of a temperature-dependent PDT dose on the treatment volume radius. APPROACH: A finite-element model, using the open-source SfePy package, was developed to simulate combined interstitial photothermal and photodynamic treatments. Results compared an additive dose model to a temperature-dependent dose model with enhanced PDT dosimetry and examined typical clinical scenarios for possible synergistic effects. RESULTS: Findings revealed that the temperature-dependent dose model could significantly expand the damage radius compared to the additive model, depending on the tissue and drug properties. CONCLUSIONS: Characterizing synergistic effects of PDT and PTT could enhance treatment planning. Future work is ongoing to implement additional variables, such as photosensitizer photobleaching, and spatial and temporally varying oxygenation.

The use of nanomaterials in advancing photodynamic therapy (PDT) for deep-seated tumors and synergy with radiotherapy.

Photodynamic therapy (PDT) has been under development for at least 40 years. Multiple studies have demonstrated significant anti-tumor efficacy with limited toxicity concerns. PDT was expected to become a major new therapeutic option in treating localized cancer. However, despite a shifting focus in oncology to aggressive local therapies, PDT has not to date gained widespread acceptance as a standard-of-care option. A major factor is the technical challenge of treating deep-seated and large tumors, due to the limited penetration and variability of the activating light in tissue. Poor tumor selectivity of PDT sensitizers has been problematic for many applications. Attempts to mitigate these limitations with the use of multiple interstitial fiberoptic catheters to deliver the light, new generations of photosensitizer with longer-wavelength activation, oxygen independence and better tumor specificity, as well as improved dosimetry and treatment planning are starting to show encouraging results. Nanomaterials used either as photosensitizers per se or to improve delivery of molecular photosensitizers is an emerging area of research. PDT can also benefit radiotherapy patients due to its complementary and potentially synergistic mechanisms-of-action, ability to treat radioresistant tumors and upregulation of anti-tumoral immune effects. Furthermore, recent advances may allow ionizing radiation energy, including high-energy X-rays, to replace external light sources, opening a novel therapeutic strategy (radioPDT), which is facilitated by novel nanomaterials. This may provide the best of both worlds by combining the precise targeting and treatment depth/volume capabilities of radiation therapy with the high therapeutic index and biological advantages of PDT, without increasing toxicities. Achieving this, however, will require novel agents, primarily developed with nanomaterials. This is under active investigation by many research groups using different approaches.

Phonozen-mediated photodynamic therapy comparing two wavelengths in a mouse model of peritoneal carcinomatosis.

BACKGROUND: This study assessed the therapeutic efficacy of intraperitoneal photodynamic therapy (PDT) using photosensitizer activation at two different wavelengths, 405 and 664 nm, in a mouse model of peritoneal carcinomatosis. METHODS: The dark and light cytotoxicity of chlorin e6-polyvinylpyrrolidone (Phonozen) were measured in vitro under 402 ± 14 and 670 ± 18 nm LED activation in bioluminescent human gastric cancer cells, MKN45-luc. Cell viability was measured at 6 h after irradiation using the PrestoBlue assay. Corresponding in vivo studies were performed in athymic nude mice by intraperitoneal injection of 1 × 106 MKN45-luc cells. PDT was performed 10 d after tumor induction and comprised intraperitoneal injection of Phonozen followed by light irradiation at 3 h, delivered by a diffusing-tip optical fiber placed in the peritoneal cavity and coupled to a 405 or 664 nm diode laser to deliver a total energy of 50 J (20 mice per cohort). Whole-body bioluminescence imaging was used to track the tumor burden after PDT out to 130 days, and 5 mice in each cohort were sacrificed at 4 h post treatment to measure the acute tumor necrosis. RESULTS: Photosensitizer dose-dependent photocytotoxicity was higher in vitro at 405 than 664 nm. In vivo, PDT reduced the tumor growth rate at both wavelengths, with no statistically significant difference. There was substantial necrosis, and median survival was significantly prolonged at both wavelengths compared with controls (46 and 46 vs. 34 days). CONCLUSIONS: Phonozen-mediated PDT results in significant cytotoxicity in vitro as well as tumor necrosis and prolonged survival in vivo following intraperitoneal light irradiation. Blue light was more photocytotoxic than red in vitro and had marginally higher efficacy in vivo.

Reduce, re-use, re-ride: Bike waste and moving towards a circular economy for sporting goods.

What happens to our sporting goods when we are done with them? Even though Sustainable Development Goal 12 focuses on responsible consumption and production, very few in the sports industry (and academy) have asked this question. With environmental degradation now a daily concern around the world, we can no longer produce and consume sporting goods without considering the end-of-use stage for these products. This study focuses on the bike and its role in global waste accumulation through various forms of planned obsolescence. Through interviews with experts in and around the bike industry and waste management, we provide insight into the environmental barriers that are structural and specific to the bike industry. We then advocate for extended producer responsibility and the circular economy as an imperfect but radical alternative future.

Formulation and Scale-up of Delamanid Nanoparticles via Emulsification for Oral Tuberculosis Treatment.

Delamanid (DLM) is a hydrophobic small molecule therapeutic used to treat drug-resistant tuberculosis (DR-TB). Due to its hydrophobicity and resulting poor aqueous solubility, formulation strategies such as amorphous solid dispersions (ASDs) have been investigated to enhance its aqueous dissolution kinetics and thereby improve oral bioavailability. However, ASD formulations are susceptible to temperature- and humidity-induced phase separation and recrystallization under harsh storage conditions typically encountered in areas with high tuberculosis incidence. Nanoencapsulation represents an alternative formulation strategy to increase aqueous dissolution kinetics while remaining stable at elevated temperature and humidity. The stabilizer layer coating the nanoparticle drug core limits the formation of large drug domains by diffusion during storage, representing an advantage over ASDs. Initial attempts to form DLM-loaded nanoparticles via precipitation-driven self-assembly were unsuccessful, as the trifluoromethyl and nitro functional groups present on DLM were thought to interfere with surface stabilizer attachment. Therefore, in this work, we investigated the nanoencapsulation of DLM via emulsification, avoiding the formation of a solid drug core and instead keeping DLM dissolved in a dichloromethane dispersed phase during nanoparticle formation. Initial emulsion formulation screening by probe-tip ultrasonication revealed that a 1:1 mass ratio of lecithin and HPMC stabilizers formed 250 nm size-stable emulsion droplets with 40% DLM loading. Scale-up studies were performed to produce nearly identical droplet size distribution at larger scale using high-pressure homogenization, a continuous and industrially scalable technique. The resulting emulsions were spray-dried to form a dried powder, and in vitro dissolution studies showed dramatically enhanced dissolution kinetics compared to both as-received crystalline DLM and micronized crystalline DLM, owing to the increased specific surface area and partially amorphous character of the DLM-loaded nanoparticles. Solid-state NMR and dissolution studies showed good physical stability of the emulsion powders during accelerated stability testing (50 °C/75% RH, open vial).

Preclinical evaluation of Raman spectroscopy for pedicular screw insertion surgical guidance in a porcine spine model.

Significance: Orthopedic surgery is frequently performed but currently lacks consensus and availability of ideal guidance methods, resulting in high variability of outcomes. Misdirected insertion of surgical instruments can lead to weak anchorage and unreliable fixation along with risk to critical structures including the spinal cord. Current methods for surgical guidance using conventional medical imaging are indirect and time-consuming with unclear advantages. Aim: The purpose of this study was to investigate the potential of intraoperative in situ near-infrared Raman spectroscopy (RS) combined with machine learning in guiding pedicular screw insertion in the spine. Approach: A portable system equipped with a hand-held RS probe was used to make fingerprint measurements on freshly excised porcine vertebrae, identifying six tissue types: bone, spinal cord, fat, cartilage, ligament, and muscle. Supervised machine learning techniques were used to train-and test on independent hold-out data subsets-a six-class model as well as two-class models engineered to distinguish bone from soft tissue. The two-class models were further tested using in vivo spectral fingerprint measurements made during intra-pedicular drilling in a porcine spine model. Results: The five-class model achieved >96% accuracy in distinguish all six tissue classes when applied onto a hold-out testing data subset. The binary classifier detecting bone versus soft tissue (all soft tissue or spinal cord only) yielded 100% accuracy. When applied onto in vivo measurements performed during interpedicular drilling, the soft tissue detection models correctly detected all spinal canal breaches. Conclusions: We provide a foundation for RS in the orthopedic surgical guidance field. It shows that RS combined with machine learning is a rapid and accurate modality capable of discriminating tissues that are typically encountered in orthopedic procedures, including pedicle screw placement. Future development of integrated RS probes and surgical instruments promises better guidance options for the orthopedic surgeon and better patient outcomes.

Exercise training augments brain function and reduces pain perception in adults with chronic pain: A systematic review of intervention studies.

Introduction: Chronic pain (CP) is a leading cause of disability worldwide. Pain may be measured using subjective questionnaires, but understanding the underlying physiology, such as brain function, could improve prognosis. Further, there has been a shift towards cost-effective lifestyle modification for the management of CP. Methods: We conducted a systematic review (Registration: #CRD42022331870) using articles retrieved from four databases (Pubmed, EMBASE, AMED, and CINAHL) to assess the effect of exercise on brain function and pain perception/quality of life in adults with CP. Results: Our search yielded 1879 articles; after exclusion, ten were included in the final review. Study participants were diagnosed with either osteoarthritis or fibromyalgia. However, two studies included "fibromyalgia and low back pain" or "fibromyalgia, back, and complex regional pain." Exercise interventions that were 12 weeks or longer (n = 8/10) altered brain function and improved pain and/or quality of life outcomes. The cortico-limbic pathway, default-mode network, and dorsolateral prefrontal cortex were key regions that experienced alterations post-intervention. All studies that reported an improvement in brain function also demonstrated an improvement in pain perception and/or quality of life. Discussion: Our review suggests that alterations in brain function, notably the cortico-limbic, default-mode and dorsolateral prefrontal cortex, may be responsible for the downstream improvements in the subjective experience of CP. Through appropriate programming (i.e., length of intervention), exercise may represent a viable option to manage CP via its positive influence on brain health.

Photodynamic and Photothermal Therapies: Synergy Opportunities for Nanomedicine.

Tumoricidal photodynamic (PDT) and photothermal (PTT) therapies harness light to eliminate cancer cells with spatiotemporal precision by either generating reactive oxygen species or increasing temperature. Great strides have been made in understanding biological effects of PDT and PTT at the cellular, vascular and tumor microenvironmental levels, as well as translating both modalities in the clinic. Emerging evidence suggests that PDT and PTT may synergize due to their different mechanisms of action, and their nonoverlapping toxicity profiles make such combination potentially efficacious. Moreover, PDT/PTT combinations have gained momentum in recent years due to the development of multimodal nanoplatforms that simultaneously incorporate photodynamically- and photothermally active agents. In this review, we discuss how combining PDT and PTT can address the limitations of each modality alone and enhance treatment safety and efficacy. We provide an overview of recent literature featuring dual PDT/PTT nanoparticles and analyze the strengths and limitations of various nanoparticle design strategies. We also detail how treatment sequence and dose may affect cellular states, tumor pathophysiology and drug delivery, ultimately shaping the treatment response. Lastly, we analyze common experimental design pitfalls that complicate preclinical assessment of PDT/PTT combinations and propose rational guidelines to elucidate the mechanisms underlying PDT/PTT interactions.

Sequential Flash NanoPrecipitation for the scalable formulation of stable core-shell nanoparticles with core loadings up to 90.

Flash NanoPrecipitation (FNP) is a scalable, single-step process that uses rapid mixing to prepare nanoparticles with a hydrophobic core and amphiphilic stabilizing shell. Because the two steps of particle self-assembly - (1) core nucleation and growth and (2) adsorption of a stabilizing polymer onto the growing core surface - occur simultaneously during FNP, nanoparticles formulated at core loadings above approximately 70% typically exhibit poor stability or do not form at all. Additionally, a fundamental limit on the concentration of total solids that can be introduced into the FNP process has been reported previously. These limits are believed to share a common mechanism: entrainment of the stabilizing polymer into the growing particle core, leading to destabilization and aggregation. Here, we demonstrate a variation of FNP which separates the nucleation and stabilization steps of particle formation into separate sequential mixers. This scheme allows the hydrophobic core to nucleate and grow in the first mixing chamber unimpeded by adsorption of the stabilizing polymer, which is later introduced to the growing nuclei in the second mixer. Using this Sequential Flash NanoPrecipitation (SNaP) technique, we formulate stable nanoparticles with up to 90% core loading by mass and at 6-fold higher total input solids concentrations than typically reported.

The Social-Ecological System of Farmers' Current Soil Carbon Management in Australian Grazing Lands.

Soil carbon sequestration programmes are a way of offsetting GHG emissions, however, it requires agricultural landholders to be engaged in such initiatives for carbon offsets to occur. Farmer engagement is low in market-based programmes for soil carbon credits in Australia. We interviewed long-term practitioners (n = 25) of rotational grazing in high-rainfall lands of New South Wales, Australia to understand their current social-ecological system (SES) of soil carbon management (SCM). The aim was to identify those components of the SES that motivate them to manage soil carbon and also influence their potential engagement in soil carbon sequestration programmes. Utilising first-tier and second-tier concepts from Ostrom's SES framework, the interview data were coded and identified a total of 51 features that characterised the farmers' SES of SCM. Network analysis of farmer interview data revealed that the current SES of SCM has low connectivity among the SES features (30%). In four workshops with interviewed farmers (n = 2) and invited service providers (n = 2) the 51 features were reviewed and participants decided on the positioning and the interactions between features that were considered to influence SCM into a causal loop diagram. Post-workshop, 10 feedback loops were identified that revealed the different and common perspectives of farmers and service providers on SCM in a consolidated causal loop diagram. Defining the SES relationships for SCM can identify the challenges and needs of stakeholders, particularly farmers, which can then be addressed to achieve local, national and international objectives, such as SCM co-benefits, GHG reduction, carbon sequestration targets and SDGs.

Discovery of Nanomolar DCAF1 Small Molecule Ligands.

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 µM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 µM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.

B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.