Organoselenium Research Articles

Effect of 3,3'-diselenodipropionic Acid on Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice.

3,3'-Diselenodipropionic acid (DSePA), a synthetic organoselenium compound, has received considerable attention because of its antioxidant properties and safety. Its protective effect against dextran sodium sulfate (DSS)-induced mouse ulcerative colitis (UC) and the role of T helper 17 (Th17) cell proliferation were investigated. Fifty C57BL/6 male mice were randomly assigned to one of five groups: control (Con), DSePA, DSS, low-dose DSePA (LSe), and high-dose DSePA (HSe). Mice in the DSS, LSe, and HSe groups drank 2% DSS to induce UC, and received normal saline, 1 and 2mg/mL DSePA solution by intraperitoneal injection, respectively. The DSePA group only received 2mg/mL DSePA solution. After 5weeks, DSS challenge induced UC in the mice, which manifested as decreased body weight, shortened colon length, the loss of goblet cells, activated proliferating cells, and multiple signs of intestinal lesions by histological observation, all of which were reversed to varying degrees by DSePA administration. DSS upregulated the colonic protein expression of the macrophage marker F4/80 and proinflammatory cytokines (IL-1β, IL-6, and TNFα), whereas DSePA administration downregulated the expression of these factors. DSS upregulated the mRNA expression of retinoic acid receptor-related orphan receptor γt (RORγt, mainly expressed in Th17 cells), IL-17A, and IL-17F and the levels of IL-17A and IL-17F in the colon, whereas DSePA administration decreased them. No difference was observed between the Con group and the DSePA group without DSS induction. Thus, DSePA administration ameliorated DSS-induced UC by regulating Th17-cell proliferation and the secretion of proinflammatory cytokines.

Conformationally Locked Carbocyclic Nucleosides Built on a 4'-Hydroxymethyl-3'-hydroxybicyclo[4.1.0]heptane Template. Stereoselective Synthesis and Antiviral Activity.

Two new families of enantiomerically pure carbocyclic nucleoside analogues based on a cyclohexane moiety with five chiral centers and a fused cyclopropyl ring have been synthesized. A highly regio- and stereoselective synthetic approach for the modular construction of the functionalized bicyclo[4.1.0]heptyl azide intermediate 6 has been established. Key steps to achieve this asymmetric synthesis involved highly diastereoselective allylic oxidation and hydroboration reactions. The first family of compounds, 1a,b and 2, presents different natural nucleobases, whereas the second one 3a-e bears functionalized 1,2,3-triazoles. These derivatives have been tested as antiviral agents, and compound 3d has shown to display moderate activity against coxsackie B4 virus.

Synthesis of vinyl selenides and tellurides: an updated review

Over the past years organochalcogen compounds have attracted the attention of many research groups due to their powerful chemical and biological activities. Vinyl selenides and tellurides have proved to be useful in organic synthesis as important tools in different reactions. Noteworthy, this important class of compounds has been shown to possess important biological assets, making them promising drug candidates. Herein, we present a comprehensive and updated review on the state of the art of the available methods developed in the last seven years to obtain vinyl selenides and vinyl tellurides. More than 130 articles were accessed, and their contents were critically revised through three main sections, highlighting the metal-free and metal-promoted synthesis of this valuable class of compounds. <br> The bibliography includes 139 references.

Expansion of the Conceptual Model for the Accumulation of Selenium in Lentic Food Chains to Include Redox-Controlled Generation and Diffusion of Selenite and Dissolved Organo-Selenium Compounds.

The controls governing the availability of reduced selenium (Se) species, namely selenite (Se[IV]) and dissolved organo-Se (DOSe), to primary producers at the sediment-water interface in depositional environments (i.e., lentic systems) were assessed through consideration of theoretical principles and field data. Selenite is generated in suboxic sediment porewater via the microbially mediated reduction of selenate (Se[IV]) and/or reductive dissolution of Se-bearing iron oxides. Field data for lentic environments demonstrate that the production of DOSe in sediment porewaters can also be redox- and depth-dependent. In this manner, the remobilization depths of Se(IV) and DOSe in depositional environments are dependent on the vertical redox gradient (dEh/dz), where deeper depths of remobilization are observed in less reducing sedimentary environments (lower dEh/dz). In turn, remobilization depth has a direct bearing on the concentration of dissolved Se(IV) and DOSe that may be realized at the sediment-water interface because the depth of reaction governs the diffusive path length, concentration gradient, and rate of diffusional transport toward the sediment-water interface. The principles that link sediment redox gradients, depth of remobilization, diffusive transport processes, and concentration of reduced Se species at the sediment-water interface have a direct bearing on the potential for Se uptake by primary producers in lentic food chains (e.g., phytoplankton, biofilms, bacteria). Overall, these processes complement the current conceptual "benthic detrital food chain" model that describes the accumulation of Se in lentic systems. Environ Toxicol Chem 2022;41:2859-2869. © 2022 SETAC.

Seleno-Metabolites and Their Precursors: A New Dawn for Several Illnesses?

Selenium (Se) is an essential element for human health as it is involved in different physiological functions. Moreover, a great number of Se compounds can be considered potential agents in the prevention and treatment of some diseases. It is widely recognized that Se activity is related to multiple factors, such as its chemical form, dose, and its metabolism. The understanding of its complex biochemistry is necessary as it has been demonstrated that the metabolites of the Se molecules used to be the ones that exert the biological activity. Therefore, the aim of this review is to summarize the recent information about its most remarkable metabolites of acknowledged biological effects: hydrogen selenide (HSe−/H2Se) and methylselenol (CH3SeH). In addition, special attention is paid to the main seleno-containing precursors of these derivatives and their role in different pathologies.

Small-Molecule Ebselen Binds to YTHDF Proteins Interfering with the Recognition of N 6-Methyladenosine-Modified RNAs.

YTHDF proteins bind the N 6-methyladenosine (m6A)-modified mRNAs, influencing their processing, stability, and translation. Therefore, the members of this protein family play crucial roles in gene regulation and several physiological and pathophysiological conditions. YTHDF proteins contain a hydrophobic pocket that accommodates the m6A embedded in the RRACH consensus sequence on mRNAs. We exploited the presence of this cage to set up an m6A-competitive assay and performed a high-throughput screen aimed at identifying ligands binding in the m6A pocket. We report the organoselenium compound ebselen as the first-in-class inhibitor of the YTHDF m6A-binding domain. Ebselen, whose interaction with YTHDF proteins was validated via orthogonal assays, cannot discriminate between the binding domains of the three YTHDF paralogs but can disrupt the interaction of the YTHDF m6A domain with the m6A-decorated mRNA targets. X-ray, mass spectrometry, and NMR studies indicate that in YTHDF1 ebselen binds close to the m6A cage, covalently to the Cys412 cysteine, or interacts reversibly depending on the reducing environment. We also showed that ebselen engages YTHDF proteins within cells, interfering with their mRNA binding. Finally, we produced a series of ebselen structural analogs that can interact with the YTHDF m6A domain, proving that ebselen expansion is amenable for developing new inhibitors. Our work demonstrates the feasibility of drugging the YTH domain in YTHDF proteins and opens new avenues for the development of disruptors of m6A recognition.

Crystal Structures of Organoselenium Compounds: Structural Descriptors for Chalcogen Bonds

AbstractLess conventional non-covalent interactions such as chalcogen bonds attract the attention of researchers in various fields (organocatalysis, material sciences, biological chemistry, …). We present here useful descriptors to easily discriminate the structures in which chalcogen bonds involving selenium are observed. Our study focused on organoselenium compounds as chalcogen bond donors and on molecular entities, as chalcogen bond acceptors, containing N, O, S, Se, and Te atoms or aromatic rings. For conventional chalcogen bonds (C–Se⋯X, with X = N, O, S, Se, or Te), the combination of the C–Se⋯X angle and the distance between X and the C–Se-C plane proved to be most relevant for identification of chalcogen bonds. For chalcogen⋯π bonds, the most relevant parameters are a combination of the C–Se⋯X angle and the angle between the C–Se bond and the normal to the aromatic ring plane.

Stereoselective Reduction of Alkynes: Synthesis of 4-Organoselenyl Quinolines.

This study describes the reaction of 2-amino arylalkynyl ketones with organoselenolates to form (Z)-vinyl selenides, which lead to 4-organoselenyl quinolines via an intramolecular condensation. Using the optimized reaction conditions, the generality of this cyclization was studied with various arylalkynyl ketones and diorganyl diselenides. The study of the reaction mechanisms led to the isolation and identification of a vinyl selenide, which was the key intermediate for this cyclization. To expand the structural diversity and to demonstrate the applicability of the 4-organoselenyl quinolines prepared, we studied their application as substrates in the cleavage of the carbon-selenium bond using n-butyllithium followed by the capture of the lithium intermediate by electrophiles and Suzuki and Sonogashira cross-coupling reactions.

Organoselenium compounds as functionalizing agents for gold nanoparticles in cancer therapy

Gold nanoparticles (AuNPs) modified with four organoselenium compounds, i.e., 4-selenocyanatoaniline (compound 1), 4,4′-diselanediyldianiline (compound 2), N-(4-selenocyanatophenyl)cinnamamide (compound 3), and N-(3-selenocyanatopropyl)cinnamamide (compound 4), were synthesized following two different approaches: direct conjugation and non-covalent immobilization onto hydrophilic and non-cytotoxic AuNPs functionalized with 3-mercapto-1-propanesulfonate (3MPS). Both free compounds and AuNPs-based systems were characterized via UV-Vis, FTIR NMR, mass spectrometry, and SR-XPS to assess their optical and structural properties. Size and colloidal stability were evaluated by DLS and ζ-potential measurements, whereas morphology at solid-state was evaluated by atomic force (AFM) and scanning electron (FESEM) microscopies. AuNPs synthesized through chemical reduction method in presence of Se-based compounds as functionalizing agents allowed the formation of aggregated NPs with little to no solubility in aqueous media. To improve their hydrophilicity and stability mixed AuNPs-3MPS-1 were synthesized. Besides, Se-loaded AuNPs-3MPS revealed to be the most suitable systems for biological studies in terms of size and colloidal stability. Selenium derivatives and AuNPs were tested in vitro via MTT assay against PC-3 (prostatic adenocarcinoma) and HCT-116 (colorectal carcinoma) cell lines. Compared to free compounds, direct functionalization onto AuNPs with formation of Au-Se covalent bond led to non-cytotoxic systems in the concentration range explored (0–100 μg/mL), whereas immobilization on AuNPs-3MPS improved the cytotoxicity of compounds 1, 3, and 4. Selective anticancer response against HCT-116 cells was obtained by AuNPs-3MPS-1. These results demonstrated that AuNPs can be used as a platform to tune the in vitro biological activity of organoselenium compounds.

Inhibition of Carbon Steel Corrosion by Some New Organic 2-Hydroselenoacetamide Derivatives in HCl Medium

This study aims to prepare 2-hydroselenoacetamide derivatives (5-8) to use some of these compounds as corrosion inhibition for carbon steel in 1 M HCl. The compound C10H10NO2Cl 1 was prepared by reacting between p-aminoacetophenone with chloroacetyl chloride, and then reacted 1 with substituted benzaldehyde to obtain the corresponding derivatives as C17H13N2O4Cl 2, C18H16NO4Cl 3 and C19H18NO4Cl 4. The last step in this study was conducted to obtain the organic hydroselenoacetamide such as C10H11NO2Se 5, C17H14N2O4Se 6, C18H17NO4Se 7, and C19H19NO4Se 8 by reacting chloroaminochalcone and sodium hydrogen selenide. All compounds were characterized by Fourier Transform Infrared Spectroscopy (FTIR), proton nuclear magnetic resonance (1H-NMR), and elemental analysis (CHN). The corrosion inhibition activity of C17H14N2O4Se 6, C18H17NO4Se 7 and C19H18NO4Cl 4 for carbon steel in 1 M HCl solution was investigated by using weight loss methods and electrochemical study. The activation energy of the corrosion reaction was also calculated. The effect of different concentrations and temperatures on inhibition efficiency was investigated. The results showed that the corrosion rate decreased with the increase of the concentration of inhibitors, while the inhibition efficiency and covered area decreased with an increase in the temperature. Polarization studies demonstrated that the inhibitors were of mixed type. The purpose of this study was to prepare, characterize and evaluate the corrosion inhibition activity of hydroselenide compounds for carbon steel in 1 M HCl.

Synthesis of Metal Chalcogenide Semiconductors by Thermal Decomposition of Organosulfur and Organoselenium Compounds.

Metal chalcogenides - because of their excellent optical and electrical properties - are important semiconductor materials for optical devices, such as solar cells, sensors, and photocatalysts. The challenges associated with metal chalcogenides are the complexity of the conventional synthesis methods and the stringent synthesis conditions. In this study, the synthesis conditions were simplified in a solvent-free synthesis method using cadmium precursor, thiourea and selenium to synthesize metal chalcogenides, such as CdS and CdSe, which have particularly suitable band gaps for the optical devices. CdSx Se1-x solid solution was successfully synthesized under molten thiourea as the reactive reaction medium at relatively low temperatures, even at 180 °C, with residual melamine derivatives in the solid phase. The luminescence properties of CdSx Se1-x and the products in the gas and solid phases were investigated. Optimization of the synthesis conditions for solid solutions of CdSx Se1-x and the role of organic compounds in the formation of metal chalcogenides are discussed.

Comparison by Life-Cycle Assessment of Alternative Processes for Carvone and Verbenone Production.

Verbenone and carvone are allylic monoterpenoid ketones with many applications in the fine chemicals industry that can be obtained, respectively, from the allylic oxidation of α-pinene and limonene over a silica-supported iron hexadecachlorinated phthalocyanine (FePcCl16-NH2-SiO2) catalyst and with t-butyl hydroperoxide (TBHP) as oxidant. As there are no reported analyses of the environmental impacts associated with catalytic transformation of terpenes into value-added products that include the steps associated with synthesis of the catalyst and several options of raw materials in the process, this contribution reports the evaluation of the environmental impacts in the conceptual process to produce verbenone and carvone considering two scenarios (SI-raw-oils and SII-purified-oils). The impact categories were evaluated using ReCiPe and IPCC methods implemented in SimaPro 9.3 software. The environmental impacts in the synthesis of the heterogeneous catalyst FePcCl16-NH2-SiO2 showed that the highest burdens in terms of environmental impact come from the use of fossil fuel energy sources and solvents, which primarily affect human health. The most significant environmental impacts associated with carvone and verbenone production are global warming and fine particulate matter formation, with fewer environmental impacts associated with the process that starts directly from turpentine and orange oils (SI-raw-oils) instead of the previously extracted α-pinene and limonene (SII-purified-oils). As TBHP was identified as a hotspot in the production process of verbenone and carvone, it is necessary to choose a more environmentally friendly and energy-efficient oxidizing agent for the oxidation of turpentine and orange oils.

Rational Catalyst Design for Higher Propene Partial Electro-oxidation Activity by Alloying Pd with Au

Selective partial oxidation of hydrocarbons to oxygenates plays a large role in the chemical industry, while falling prices for electricity from renewable sources make electrification of such industrial chemical processes relevant. The oxidation of propene is an interesting model system as propene can be oxidized in two different positions, allowing for insights into the reaction mechanism. On Pd, a layer of adsorbates formed in situ governs the reaction by steering reactant adsorption to achieve high selectivity for allyl oxidation, albeit largely inhibiting the reaction rate. Through rational catalyst design, we demonstrate that alloying reactive Pd with inert Au influences the adsorbate layer formation, enhancing activity while maintaining high selectivity toward allyl oxidation. We obtain mechanistic insights with a combination of ab initio computational modeling and electrochemical measurements with ex situ product quantification and online mass spectrometry. Using a statistical approach, we explore the correlation of the Au:Pd ratio with Pd surface cluster size and density, which determine the properties of the adsorbate layer and thus the reaction outcome. We report an activity enhancement by a factor 2.4 with 10% Au in Pd and propose that (i) activity is maximized at potentials just before Pd cluster oxidation and (ii) the optimal catalyst surface contains approximately one Au every six Pd atoms, statistically most frequent at the nominal alloy composition Au14Pd86.

Enzyme-catalyzed allylic oxidation reactions: A mini-review.

Chiral allylic oxidized products play an increasingly important role in the pharmaceutical, agrochemical, and pharmaceutical industries. Biocatalytic C–H oxyfunctionalization to synthesize allylic oxidized products has attracted great attention in recent years, with the ability to simplify synthetic approaches toward complex compounds. As a result, scientists have found some new enzymes and mutants through techniques of gene mining and enzyme-directed evolution in recent years. This review summarizes the recent developments in biocatalytic selective oxidation of olefins by different kinds of biocatalysts.

Construction of the Skeleton of Lucidumone.

The skeleton of lucidumone was constructed through oxidative dearomatization/intramolecular Diels-Alder reaction, Cu-mediated remote C-H hydroxylation, allyl oxidation, acid-promoted dynamic kinetic resolution cyclization, and benzylic oxidation.

Inhibition of H1N1 Influenza Virus-induced Apoptosis by Ebselen Through ROS-mediated ATM/ATR Signaling Pathways.

Influenza A viruses can cause global outbreaks and seasonal pandemics. However, the use of conventional anti-influenza drugs leads to an increase in drug-resistant mutations in influenza viruses worldwide. Therefore, numerous studies have focused on developing effective anti-influenza drugs. It is feasible to treat influenza by targeting influenza-mediated oxidative damage. Ebselen is a synthetic organoselenium compound which provides glutathione peroxidase-like activity. It has been shown to play a role in anti-influenza therapy, but the mechanism remains to be further explored. This experiment verified the anti-influenza effect of ebselen. CCK-8 and PCR showed that ebselen had a significant inhibitory effect on virus replication compared with the virus group. In addition, the mechanistic investigations revealed that ebselen could inhibit influenza-mediated apoptosis, mitochondrial damage, accumulation of reactive oxygen species, and DNA breakage. At the same time, ebselen significantly inhibited the phosphorylation of ATM and ATR and promoted the activation of PARP and Caspase-3. Ebselen, on the other hand, reduced the inflammatory response caused by influenza. These results suggest that ebselen is a promising inhibitor for H1N1.

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Structural rearrangement of organs of white mice vaccinated with Yersinia pestis EV in combination with organoselenium compound 974zh

Introduction. An urgent direction is the search for means that increase the effectiveness of the Y. pestis EV NIIEG vaccine and reduce the side pathological manifestations caused by it. Organoselenium compounds have immunotropic properties and increase the antioxidant potential of the body, as well as have an antidystrophic effect and an antiallergic effect. Materials of the study of the immunomodulating effect of the experimental selenium-containing compound 2,6-dipyridinium-9-selenabicyclo[3.3.1]nonane dibromide (974zh) on the macroorganism of laboratory animals are presented.The aim. To evaluate the effect of the organoselenium compound 974zh on the structural rearrangement of the organs of experimental animals in the dynamics of the vaccine process caused by Y. pestis EV.Methods. The study was carried out on 70 certified outbred white mice. Histological material (thymus, lymph nodes, spleen, adrenal glands, liver) was embedded in paraffin, semi-thin sections were stained with hematoxylin and eosin, thionin, and by the Brachet method. The severity of pathological changes in the liver and adrenal glands, proliferation of plasma cells and structural changes in immunocompetent organs (thymus, lymph nodes and spleen) were assessed. Microphotography and quantitative analysis were performed using MoticImagesPlus 2.0. Statistical processing was carried out using the computer program Statistica.Results. It has been established that the combined administration of 974zh and Y. pestis EV leads to morphological and functional restructuring of immunocompetent organs, enhances the proliferation of plasma cells in the spleen and lymph nodes, and eliminates negative changes in the liver and adrenal glands. Conclusion. Thus, the 974zh preparation enhances the immunogenic effect of the Y. pestis EV vaccine strain, increasing the T- and B-dependent zones of the spleen and lymph nodes, increasing the proliferation of plasma cells, and also significantly reduces pathological changes in the liver and adrenal glands.

Abstract 5451: New organoselenium compounds with cytotoxic activity in vitro and in vivo towards colon cancer

Abstract Colon cancer is currently the third most common diagnosed cancer and the second leading cause of cancer death worldwide. The inclusion of a selenium atom (Se) in organic molecules has been shown to be a valid approximation in the design of novel chemotherapeutic agents with antitumoral activity. On the other hand, non-steroidal anti-inflammatory drugs (NSAIDs) have gained interest in recent years in terms of their chemopreventive and chemotherapeutic use for cancer treatment whether they are evaluated alone, as a combination therapy, or in the form of structurally modified analogs. Considering these findings, we have designed five novel NSAID derivatives containing Se in their structure. The cytotoxicity and selectivity of the new compounds were evaluated in a panel of 10 cancer cell lines including breast, prostate, lung, and colon cancer, and in two non-malignant cell lines. Compound 5 was the most cytotoxic derivative with IC50 values below 10 µM in all the cancer cell lines tested, and it was also the most selectively toxic towards cancer cells while sparing the non-malignant cell lines. The efficacy of compound 5 in vivo was assessed in a subcutaneous colon cancer xenograft mouse model and it showed a significant inhibition of the tumor growth. Taken together, this work supports that the novel Se-NSAID combination provides a feasible frame to develop new agents with potent antitumoral properties Citation Format: Sandra Ramos-Inza, Cesar Aliaga, Asif Raza, Ignacio Encío, Arun Sharma, Carmen Sanmartín, Daniel Plano. New organoselenium compounds with cytotoxic activity in vitro and in vivo towards colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5451.

Abstract 5449: Novel seleno-biotin compound inhibits viability of and induces reactive oxygen species (ROS)-mediated apoptosis in ovarian cancer cells

Abstract Ovarian cancer is one of the most common cancers in women and even with the currently available treatment options, including surgery, radiation, and chemotherapy, it caused 13,940 deaths in US alone in 2020. Thus, there is a continuous need for developing novel approaches for the treatment of ovarian cancer, particularly drug resistant ovarian cancer, as ovarian cancer most adversely affects the lives patients. Here in, we have designed seleno-biotin derivatives as potential therapeutics for ovarian cancer. The rational for designing these hybrid small molecules is two fold: (i) The biotin receptors are up-regulated in various carcinomas including ovarian cancer cells while being expressed at low levels in normal cells. Due to the high affinity of biotin towards BR, biotin has been used as a conjugate for several targeted imaging, sensing, and delivery in vitro and in vivo. (ii) Organoselenium compounds with appropriate selenium moieties have shown therapeutic efficacy in several pre-clinical cancer models. Therefore, we designed several analogs of biotin by conjugating selenium moieties connected through ester, selenoester, or amide functionalities and their cytotoxicities were assessed using four different ovarian cancer cell lines. Ester-linked biotin-selenocyanate compound 2, out of the other analogs, in direct comparison to biotin alone, more effectively reduced the cell viability (IC50 9.8-18.5 µM against all the tested cell lines) and induced apoptosis in ovarian cancer cells in dose dependent manner as demonstrated by the cell viability assay. It showed three times more potency (IC50 14.08 µM) than standard drugs 5-FU (IC50 48.4 µM) and cisplatin (IC50 41.0 µM) against drug-resistant Hey A8 cancer cells and three times more activity with an IC50 value of 9.8 µM as compared to 5-FU (IC50 25.92 µM) against ES-2 cells. The above findings were supported by trypan blue dye exclusion assay, Annexin V/7-AAD, Caspase 3/7 apoptosis assays and Western blotting of apoptotic proteins. Compound 2 effectively caused cell cycle arrest of the treated OVCAR-3 cells in S-phase of the cell cycle, thus causing regulatory changes in the cell cycle proteins, as evident by Western blotting. In addition, compound 2 redox cycles was demonstrated by DCFDA based reactive oxygen species estimation. These experiments demonstrate that selenium modified biotin which contains a covalently attached redox cycling selenide group has the potential for human therapeutic applications against ovarian and other cancers over-expressing biotin receptors. Citation Format: Asif Raza, Amandeep Singh, Amin Shantu, L. Mallory Boylan, Julian E. Spallholz, Arun Sharma. Novel seleno-biotin compound inhibits viability of and induces reactive oxygen species (ROS)-mediated apoptosis in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5449.