Al-modified (chemical grafting) SBA-15 (SiO2/Al2O3 = 5 mass ratio) materials were used as noble metal (NM, monometallic Pt or Pd and bimetallic Pd/Pt = 4, 0.5 wt % loading) carriers. The materials were studied by XRF, N-2 physisorption, XRD, TPR, pyridine thermodesorption FTIR, and STEM (HAADF). Hydrogenating properties were tested in naphthalene (N) conversion; meanwhile, dibenzothiophene (80 ppm) was added in some experiments to evaluate the thioresistance of prepared catalysts. Al-incorporation provided enhanced Lewis and Br & oslash;nsted acidity to pristine SBA-15 due to alumina-like domains that contributed to Pt dispersion reflected in augmented hydrogenation. The Pt-based catalyst was the most active in N saturation (T = 290 degrees C, P = 6.97 MPa), whereas the Pd/Pt (4/1) formulation had enhanced thioresistance probably due to NM alloying (electron transfer in Pt-Pd core-shell particles) in conjunction with weak Br & oslash;nsted acidity (Si-O-Al bonds, electron transfer from NM) that provided additional sites for aromatic adsorption. Enhanced thioresistance is crucial for aromatic saturation of NM catalysts aimed at second-stage polishing of ultralow S diesel.

Strategies followed to improve SBA-15 surface (essentially inert) included modifications by adding acidic or basic (or both) species during or after silica synthesis. Amphoteric properties are especially important, as some reactions (alcohol dehydration, for instance) require both types of sites to efficiently take place. In this work, single Zr (nominal 3, 5, and 10 wt%, as ZrOCl2•8H2O) direct addition during SBA-15 synthesis was used to impart amphoteric characteristics (as determined by NH3 and CO2 TPD) to mesostructured SiO2 matrices. Additional materials characterization included textural (N2 physisorption) and structural (XRD, FTIR, and UV–Vis spectroscopies, and HRTEM as well) studies. Actual solids composition was also determined (EDS). The degree of Zr incorporation into mesoporous silica was enhanced with nominal content in binary formulations, although not necessarily integrated into SBA-15 walls forming Zr-O-Si linkages. It seemed that single ZrO2 domains (framework and extra-framework) could provide suitable amphoteric properties by significantly increasing the number and strength of both acid and basic sites (especially formulations containing nominal 5 wt% Zr), as to those over mesostructured silica matrices. Also, potentially deleterious strong acid sites were avoided. The binary oxides present great potential to be applied in reactions requiring vicinal acid–base pairs (alcohol dehydration, for instance).

Lanthanum (La) integration (at various nominal contents) in SBA-15 prepared under acidic medium was intended from corresponding direct nitrate addition during mesoporous silica formation. Materials were impregnated with Pt (1.5 wt%) and studied through several textural (N2 physisorption), structural (XRD, TG-DTG), and surface (FTIR, STEM-HAADF, SEM-EDS, NH3, and CO2 TPD) instrumental techniques. Pt-impregnated solids were tested in phenol hydrodeoxygenation (HDO, T = 250 °C, 3.2 MPa, batch reactor, n-decane as solvent). Catalytic activity (in pseudo-first-order kinetic constant, kHDO basis) was not directly related to Pt dispersion, which was not determined by nominal rare earth content. Determining the actual composition of modified SBA-15 materials is crucial in reaching sound conclusions regarding their physicochemical properties, especially when La modifier is directly added during mesoporous matrix formation, where efficient interaction among constituents could be difficult to get. Otherwise, results from some characterization techniques (N2 physisorption and FTIR, for instance) could be misleading and even contradictory. Indeed, extant modifier precursors, when under SBA-15 synthesis conditions, could affect the properties of prepared materials even though they were absent in obtained formulations. Performing simple compositional analysis could eliminate uncertainties regarding the role of various modifiers on characteristics of final catalysts. However, several groups have failed in doing so.

In this study, opal–magnetite photocatalysts based on SiO2 artificial opal crystals infiltrated with different concentrations of Fe3O4 nanoparticles (NPs) were synthesized using a combination of lateral infiltration and co-assembly methods. By adjusting the concentration of Fe3O4 NPs in the SiO2 opal crystal, the energy band gap (Eg) was tuned to enable efficient degradation of methylene blue (MB) under visible light (410 nm and 575 nm). The photocatalytic process involved two stages: MB adsorption on the surface due to charge differences in the composite film and subsequent degradation through oxidative radicals on the catalyst’s surface. The developed material exhibited potential for applications in water remediation.

The stability of the catalyst used in hydrodeoxygenation (HDO) of biomass-derived oils needs improvement. La has been applied in delaying Al2O3 phase-change under reaction conditions. Lanthanum (0.5-8 wt.%)-gamma-alumina was studied as Pt (1 wt.%) carrier aimed at guaiacol (GUA) HDO. Materials characterization included N-2 physisorption, X-ray diffraction (XRD), thermal analysis, FTIR, UV-vis, and TPR. Solids pore size (similar to 8-10 nm) was suitable for GUA (kinetic diameter similar to 0.668 nm) hydrotreating. Mixed carriers were amorphous (XRD), suggesting well-dispersed La domains; meanwhile, carbonates/bicarbonates were formed (from CO2) due to the basic surface properties of modified supports (FTIR). That could impart catalyst stability by inhibiting coking through the passivation of Lewis acidity on Al2O3. Pt reducibility increased with La loading in various formulations. However, that was not reflected in enhanced GUA HDO (T = 488 K and P = 3.2 MPa, batch reactor), presumably due to the strong metal-support interaction (SMSI), where LaOx covered the metallic Pt particle surface. GUA HDO on various catalysts was approximated by pseudo-first-order kinetics (integral regime, k), where deviations were observed as La loading increased, presumably by an SMSI state that could affect the rate-determining step of the reaction mechanism. Basic sites provided by rare-earth could contribute to altering HDO reaction pathways as well. At 1 wt.% rare-earth, GUA HDO was maximized (k similar to 25% higher than that on Pt/Al2O3), with that material also exhibiting similar deoxygenation (85%-90% at total GUA conversion) to the latter Pt over pristine alumina. Conversely, both parameters significantly diminished over the catalyst of the highest La content. Materials at low rare-earth concentrations deserve further studies focused on catalyst stability under HDO conditions.

Tables S1-S3, Figures S1-S5

Saccharose (SA) and citric acid (CA) were used as additives in P-doped CoMo/Al2O3 catalysts (Mo, Co and P at 12, 3, and 1.6 wt%, respectively) intended to be applied in guaiacol hydrodeoxygenation (HDO). One-pot impregnating solutions were prepared by MoO3 digestion in aqueous H3PO4, followed by C4H6CoO4•4H2O addition. Organics were added (SA/Co=1, CA/Co=2) at two different preparation stages to assess the effect of that step on catalysts properties. Method I: SA or CA was added in as-prepared Co-Mo-P impregnating solution, followed by pore-filling impregnation of alumina support. Method II: SA or CA at aforementioned concentrations was impregnated on the pristine carrier, followed by drying (120 °C, 2 h). Co-Mo-P phases were further deposited on modified supports through corresponding one-pot solutions. All materials were dried (120 °C) but not calcined. Cobalt complexation by CA and Mo-blue LMCT complex formation (SA-modified solids) were identified (UV-vis, oxidic samples). Partially reduced molybdenum (Mo6+ => Mo5+, by XPS) was observed after either organics addition that effect being more evident in SA-modified solids. Materials were gas-phase sulphided (H2S/H2 10%, 400 °C, 2 h) then studied by HR-TEM. Co-Mo-P phases impregnation in one-pot solution simultaneously deposited with SA rendered the materials of the highest MoS2 dispersion.

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against WT ALK and many types of ALK resistance mutations, e.g., G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC50 <10 nmol/L) WT ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were approximately 66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against WT ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.

Oil-derived middle distillates (straight-run gas oil and mixture with light cycle oil and coker gas oil) for Ultra-Low Sulfur Diesel (ULSD) production by HyDroTreating (HDT) were pretreated by selective Nitrogen Organic Compounds (NOC) adsorption. Highly crystalline Metal-Organic Framework (MOF) MIL-101(Cr) prepared with propylene oxide (proton scavenger) as textural improver was used to that end. MOF was characterized by N 2 physisorption, X-ray diffraction, thermal analysis, infrared, Raman and UV-vis spectroscopies, and electron microscopy (SEM and HR-TEM). NOC removal was carried out at room temperature and atmospheric pressure, the adsorbent being easily regenerable under mild conditions. Extruded MOF efficiently removed NOC from real feedstocks to concentrations ~ 80 ppm which allowed ULSD production at much milder conditions to those used during pristine feedstocks HDT. Operating temperature could be significantly diminished (from 350 to 330 °C, at 56 kg cm −2 (5.77 MPa), LHSV = 1.5 h −1 , H 2 /oil = 2500 ft 3 bbl −1 (445 m 3 m −3 )) which could notably prolong cycle life of NiMo/Al 2 O 3 formulation used.

Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5'-untranslated region (5'-UTR) of mRNA to facilitate ribosome scanning and translation initiation. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and specific polypurine sequence motifs and has been reported to inhibit translation of driver oncogenes in models of lymphoma. Here we report the identification of zotatifin binding motifs in the 5'-UTRs of HER2 and FGFR1/2 Receptor Tyrosine Kinases (RTKs). Dysregulation of HER2 or FGFR1/2 in human cancers leads to activation of the PI3K/AKT and RAS/ERK signaling pathways, thus enhancing eIF4A activity and promoting the translation of select oncogenes that are required for tumor cell growth and survival. In solid tumor models driven by alterations in HER2 or FGFR1/2, downregulation of oncoprotein expression by zotatifin induces sustained pathway-dependent anti-tumor activity resulting in potent inhibition of cell proliferation, induction of apoptosis, and significant in vivo tumor growth inhibition or regression. Sensitivity of RTK-driven tumor models to zotatifin correlated with high basal levels of mTOR activity and elevated translational capacity highlighting the unique circuitry generated by the RTK-driven signaling pathway. This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.

Abstract Three generations of ALK inhibitors are approved for the treatment of ALK+ NSCLC but their efficacy is often limited by ALK resistance mutations. The solvent front mutation G1202R and gatekeeper mutation L1196M are major resistance mechanisms to the first two generations of inhibitors. Patients treated with second generation inhibitors are reported to progress with multiple mutations on separate alleles (mutations in trans). In contrast, 35 - 48% of patients treated with lorlatinib progress with multiple mutations on the same allele (compound mutations, mutations in cis). TPX-0131 is an ALK inhibitor with a compact macrocyclic structure designed to bind completely within the ATP binding boundary and overcome a spectrum of single and compound ALK resistant mutations. TPX-0131 was profiled against previous generations of ALK inhibitors both in vitro and in vivo. In biochemical assays, TPX-0131 potently inhibits (IC50 <10 nM) wild type (WT) ALK and 26 ALK mutations (single and compound). Cell proliferation assays of WT, single mutations, and compound mutations were used to evaluate TPX-0131 relative to previous generations of ALK inhibitions (crizotinib, alectinib, brigatinib, ceritinib, lorlatinib). TPX-0131 is more potent against WT EML4-ALK (IC50 = 0.4 nM) than previous generations of ALK inhibitors (2-fold, lorlatinib; 10 - 30-fold, second generation inhibitors; >100-fold, crizotinib). TPX-0131 potently inhibits EML4-ALK harboring a G1202R solvent front mutation (IC50 = 0.2 nM) which is >100-fold more potent than previous generations of ALK inhibitors. TPX-0131 potently inhibits ALK harboring a gatekeeper mutation (IC50 = 0.5 nM) and is >10-fold more potent than previous generations of ALK inhibitors. TPX-0131 potently inhibits ALK with a L1198F hinge area mutation (IC50 = 0.2 nM) which is 87 - 3000-fold more potent than previous generations of ALK inhibitors. TPX-0131 is the most potent inhibitor against nine EML4-ALK double and triple compound mutations (6 with IC50 < 1 nM, 3 with IC50 1.6 - 14.9 nM). Evaluation of ALK phosphorylation as a pharmacodynamic marker in tumors showed potent ALK inhibition by TPX-0131 that correlated with TPX-0131 exposure. In Ba/F3 cell-derived xenograft tumor models with EML4-ALK mutations, TPX-0131 (2, 5, 10 mg/kg BID) demonstrated robust anti-tumor activity in the G1202R model (64%, 120%, 200% TGI), G1202R/L1198F model (complete regression, all doses), and G1202R/L1196M model (44%, 83% and 200% TGI). In contrast, lorlatinib (5 mg/kg BID) caused 31% TGI in the G1202R/L1198F model and did not have statistically significant TGI in the G1202R/L1196M model. Taken together, TPX-0131 is a next generation ALK inhibitor that has preclinical potency against WT ALK as well as a broad spectrum of acquired resistance mutations, especially compound mutations, which currently lack any effective ALK inhibitor therapy. Citation Format: Brion W. Murray, Dayong Zhai, Wei Deng, Evan Rogers, Xin Zhang, Jane Ung, Vivian Nguyen, Han Zhang, Maria Barrera, Ana Parra, Jessica Cowell, Dong Lee, Herve Aloysius. TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1469.

Abstract The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5′-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.

The Pickering emulsion polymerization of styrene (St), divinylbenzene (DVB) as a crosslinking agent, and sodium 4-vinyl benzene sulfonate (VBS) used for in situ surface-modification of silica nanoparticles (SNps) was investigated.At 1.0 wt% DVB, amphiphilic SNps with hydrophobic patches were formed, further self-assembling into copolymer-SNps clusters occurred.Subsequently, these clusters grow by monomer swelling to finally lead to the formation of core-shell polymer microspheres.Unlike the hydrophilic patchy SNps, at 2.0 and 3.0 wt% DVB, surface-patterned SNps with higher effective hydrophobicity do not self-assemble in the water phase but rather lead to the formation of monoliths.The polymerization mechanisms related to the formation of polymer silica-coated microspheres hybrid-materials, or percolated monoliths with bi-continuous porosity, formed by interfacially jammed emulsion gel (bijels) templates, are discussed herein.

Pt (0.5, 1 and 1.5 wt%) was impregnated by incipient wetness on SBA-15 and corresponding Ga-modified (3, 5, 10 and 20 wt%) composites. Gallium nitrate was incorporated directly during the mesoporous siliceous network synthesis. Materials were characterized by N2 physisorption, X-ray diffraction, Fourier transformed infrared spectroscopy, scanning electron microscopy and transmission electron microscopy. SBA-15 had surface area greater than 800 m²/g that decreased by Ga incorporation in binary materials. It seemed that tetrahedral gallium was well-incorporated into mesoporous silica walls. Pt dispersion slightly diminished (as to that on SBA-15) by augmenting Ga concentration in composites. Corresponding pore size maxima shifted to lower diameters (as to that of non-impregnated supports) after platinum loading suggesting Pt crystals inside pores of SBA-15 and Ga-modified carriers. Large cubic platinum crystals were observed over all prepared materials probably due to sintering (during calcining at 500 °C) of metallic particles weakly interacting with the carriers surface. After materials annealing (500 °C under static air) metallic platinum was evidenced (by XRD) pointing out to noble metal reduction that could be facilitated by decomposition of organic remains from Si alkoxide used during supports synthesis which presence was ascertained by FTIR.

Alumina-lantana (2.5, 5, 7.5 and 10 wt% La) mixed oxides of suitable texture to be applied as supports of catalysts for hydrodesulfurization of FCC naphtha-range oil-derived distillates were prepared by rare-earth pore-filling impregnation through corresponding nitrate. Co, Mo and P were deposited on binary carriers by one-pot simultaneous impregnation method used during commercial hydrotreating catalysts preparation. Materials were characterized by N2 physisorption, XRD, SEM–EDS, adsorbed CO2 FTIR (basicity measurements), Raman and UV–vis spectroscopies. Sulfided catalysts were studied by chemical composition (EDAX) and HR-TEM. In general, amount and strength of surface basic sites increased with rare-earth content in binary carriers at 5 wt% and higher. Deposited molybdates dispersion augmented with lanthanum content in carriers. However, progressively increasing rare-earth loading on supports was detrimental on gas-phase thiophene HDS (523–563 K, steady-state fixed-bed plug-flow reactor operating at atmospheric pressure). Hardly sulfidable tetrahedral Mo species could be originated by decomposition of heteropolymolybdates originally present in one-pot acidic (pH ~ 1.9) Co–Mo–P solutions by impregnating at basic conditions in pores of La-modified carriers. At isoconversion (~ 10%) rare-earth containing sulfided CoMo catalysts had decreased yield to fully saturated n-butane as to the material supported on pristine alumina.

Abstract Anaplastic lymphoma kinase (ALK) gene rearrangements occur in up to 7% of patients with non-small cell lung cancer (NSCLC) with the majority as EML4-ALK fusions. Crizotinib (first generation ALK inhibitor) was the first approved ALK inhibitor for the treatment of ALK-positive metastatic non-small cell lung cancer. However, development of resistance to crizotinib caused by secondary kinase domain mutations, bypass signaling, or morphology changes occurs. Second generation ALK inhibitors alectinib, ceritinib, and brigatinib were able to overcome the majority of ALK resistant mutations (L1196M, G1269A and F1174L) acquired with crizotinib. The solvent front mutation (SFM) G1202R is a common resistant mutation to crizotinib and the second generation ALK inhibitors. Lorlatinib, a third generation ALK inhibitor, can overcome G1202R resistance with moderate IC50 values of 40 - 60 nM in cell-based assays. Although, compound mutations such as ones with both gatekeeper and solvent front mutations (L1196M/G1202R) are refractory to lorlatinib, representing an unmet medical need. TPX-0131 is a next generation ALK inhibitor designed with a compact macrocyclic structure that can bind completely within the ATP binding boundary to overcome a variety of ALK resistant mutations, especially SFM G1202R and compound mutations L1196M/G1202R. TPX-0131 potently inhibits wildtype (WT) ALK and over 20 different ALK mutations with IC50 values <5 nM when tested in enzymatic kinase assays in the presence of 10 μM of ATP. In cell proliferation assays, TPX-0131 exhibited comparable antiproliferation activity to the most potent ALK inhibitor lorlatinib in Ba/F3 cells engineered with EML4-ALK WT. Importantly, TPX-0131 is more than 100-fold more potent against G1202R than lorlatinib in cell proliferation assays. Furthermore, TPX-0131 demonstrated antiproliferation IC50 values <2 nM in Ba/F3 cell models engineered with compound mutations including L1196M/G1202R, L1198F/G1202R, L1196M/L1198F, and C1156Y/G1202R, while lorlatinib and other ALK inhibitors are not active (IC50s >1 μM). Taken together, TPX-0131 is a next generation ALK inhibitor that can overcome a broad spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations (e.g. L1196M/G1202R). The nonclinical pharmacology profile of TPX-0131 warrants further preclinical investigation. Citation Format: J. Jean Cui, Evan Rogers, Dayong Zhai, Wei Deng, Jane Ung, Vivian Nguyen, Han Zhang, Xin Zhang, Ana Parra, Maria Barrera, Dong Lee, Brion Murray. TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5226.

Multiple research studies revealed the benefits of adopting a growth mindset of intelligence for students of all ages. However, few studies have investigated the advantage of having a growth mindset of personality or having grit on academic performance. Therefore, this study investigated the influence of grit and implicit theories of intelligence and personality on academic performance in fifth through eighth-grade students. Our hypothesis is that a relatively higher level of grit as well as a growth mindset would result in better academic success. Students were tested in their respective classrooms using questionnaires for grit, mindset of intelligence and mindset of personality. Quarter grades and standardized scores were obtained for all students on topics such as English, reading, language, math and science. Growth mindset of intelligence and growth mindset of personality provided a selective advantage academically to students on classroom grades and on standardized testing, particularly in verbal areas such as English, reading and language. Furthermore, mindset of intelligence predicted significant change in standardized math scores. Grit did not affect academic performance. Our results suggest that educational institutions would benefit from mindset interventions promoting a growth mindset of intelligence and personality in students.

Background: Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5′-untranslated region (5′-UTR) of mRNA facilitating ribosome scanning and translation initiation. Alterations in receptor tyrosine kinases (RTKs) lead to activation of the RAS/MAPK and PI3K/mTOR signaling pathways, enhance eIF4A activity, and promote the translation of select oncogenes that are required for tumor cell proliferation and survival. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and sequence specific polypurine motifs in the 5′-UTR of zotatifin target genes, such as FGFR1/2 and HER2. Here we show that activation of eIF4A through RTK alterations along with downregulation of RTK protein expression by zotatifin creates a pathway dependency that drives selectivity to zotatifin treatment. Since many RTKs act as resistance mechanisms to current cancer therapies, regulation of RTKs by zotatifin also provides an effective drug combination strategy.

Abstract Mutations in KRAS are among the most common oncogenic lesions across a variety of human cancers. Activation of KRAS directs signaling via the MAPK and PI3K pathways to promote tumor growth. One outcome of enhanced KRAS signaling is the induction of mRNA translation by eIF4A, eIF4E, and eIF4G, which together comprise the eIF4F complex. eIF4A is an RNA helicase that functions to unwind elements in the 5'-untranslated region (UTR) of mRNAs to facilitate scanning of the 40S ribosomal subunit. eFT226 is a highly potent and selective inhibitor of eIF4A that functions by forming a ternary complex between eIF4A, eFT226 and specific polypurine motifs in the 5'-UTR of select mRNAs, thus blocking ribosome scanning and inhibiting mRNA translation. This polypurine sequence motif is highly enriched in the 5'-UTR of eFT226 target genes, many of which are known proto-oncogenes. Translational profiling revealed KRAS to be a target of eFT226 and 5'-UTR sequence analysis of KRAS mRNA identified the polypurine regulatory motif, which imparts sensitivity to eFT226 mediated inhibition of translation. In cell-based reporter assays used to monitor translation, mutation of the KRAS 5'-UTR polypurine motifs resulted in a 10-fold decrease in sensitivity to eFT226 relative to the wild-type sequence. In a cell panel screen for in vitro apoptosis induction by eFT226, the most sensitive models were enriched for cell lines driven by KRAS mutations. Consistent with these results, treatment with eFT226 decreased KRAS protein levels, repressed downstream MAPK signaling, inhibited cell proliferation, and induced apoptosis in a collection of non-small cell lung, colorectal and pancreatic KRAS mutant cancer cell lines. The ability of eFT226 to block tumor cell growth and induce apoptosis is independent of the specific KRAS mutation present (e.g. G12C/V, G13D, Q61H/L) suggesting that eFT226 could be broadly efficacious in treating tumors with activating KRAS mutations. Treatment of KRAS mutant solid tumor xenografts with eFT226 as a monotherapy significantly inhibited tumor growth. Together, these results highlight the ability of eFT226 to inhibit growth and promote apoptosis in KRAS mutant tumors and support the clinical development of eFT226 in KRAS driven tumors. A clinical trial evaluating eFT226 in patients with solid tumor malignancies has initiated. Citation Format: Craig R. Stumpf, Vikas K. Goel, Joan Chen, Jocelyn Staunton, Emily M. Santori, Maria Barrera, Haleigh Howard, Kevin R. Webster, Gary G. Chiang, Peggy A. Thompson. Inhibition of eIF4A by eFT226 blocks KRAS mutant tumor growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1955.

Abstract Aberrant protein translation plays a role in the pathogenesis of multiple solid tumors and hematologic malignancies. The translation initiation factor eIF4E is essential for the translation of m7G-capped mRNA and is a key point of convergence for several signaling pathways, such as PI3K/mTOR and MAPK, which are intimately involved in tumor cell growth and survival. As such, eIF4E has generated intense interest as a target for anticancer drug discovery. We have designed a series of potent, selective, and orally available m7G cap-competitive inhibitors of eIF4E (eFT-4Ei) with favorable drug-like properties. These inhibitors bind free eIF4E, eIF4E-4EBP and eIF4E-eIF4F complexes within tumor cells. Ribosomal profiling of eIF4E inhibitor-treated tumor cells has identified a subset of translationally regulated target genes that overlap with mTORC1/2 regulated genes, but also include a larger set of unique translationally regulated target mRNAs that are enriched for 5'-TOP, PRTE and CERT sequence elements in their 5'-untranslated regions. eIF4E inhibition results in potent antiproliferative activity and induction of apoptosis in a subset of tumor cell lines. Consistent with this observation, our eIF4E inhibitors show some similarities, yet several important differences from existing mTORC1 or mTORC1/2 dual inhibitors in both cellular and physiologic assays. Finally, significant antitumor efficacy was observed with eIF4E inhibition in both solid tumor and hematologic xenografts in vivo. Taken together, these results highlight the potential of targeting eIF4E as a novel and differentiated therapeutic strategy to treat cancer. Citation Format: Gregory S. Parker, Ivy N.J. Hung, Jocelyn Staunton, Maria Barrera, Eric Sung, Ana Parra, Craig R. Stumpf, Joan Chen, Peggy A. Thompson, Andreas Nevarez, Christopher J. Wegerski, Jeff Clarine, Samuel Sperry, Alan Xiang, Christian Nilewski, Garrick K. Packard, Kaveri Urklalan, Takasuke Mukaiyama, Theo Michels, Justin T. Ernst, Paul A. Sprengeler, Siegfried H. Reich, Gary G. Chiang, Kevin R. Webster. Targeting PI3K/mTOR signaling with potent, selective and orally-available small-molecule inhibitors of eIF4E [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B33.