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Multiple myeloma with 1q21 amplification is highly sensitive to MCL-1 targeting
No full textProsurvival BCL-2 family proteins are potent inhibitors of apoptosis and often overexpressed in lymphoid malignancies. In multiple myeloma (MM), MCL-1 expression contributes to survival of malignant plasma cells, and overexpression correlates with poor prognosis. In this study, we investigated whether sensitivity to the novel MCL-1 inhibitor S63845 could be predicted using cytogenetics, focusing on amplification of 1q21, the chromosomal region that contains the MCL1 locus. In addition, we studied the relation of MCL-1 inhibitor sensitivity with other diagnostic characteristics and BCL-2 family protein expression. In 31 human myeloma cell lines and in bone marrow aspirates from 47 newly diagnosed MM patients, we measured the effect of S63845 alone, or combined with BCL-2 inhibitor ABT-199 (venetoclax), and BCL-XL inhibitor A-1155463 or A-1331852 on cell viability. We demonstrated for the first time that MM cells from patients with 1q21 amplification are significantly more sensitive to inhibition of MCL-1. We suggest that this increased sensitivity results from high relative MCL1 expression resulting from amplification of 1q21. Additionally, and partially independent from 1q21 status, high serum b2 microglobulin level and presence of renal insufficiency correlated with increased sensitivity to MCL-1 inhibitor treatment. Combining S63845 with other BH3 mimetics synergistically enhanced apoptosis compared with single inhibitors, and sensitivity to inhibitor combinations was found in a large proportion of MM insensitive to MCL-1 inhibition alone. Collectively, our data indicate that amplification of 1q21 identifies an MM subset highly sensitive to MCL-1 inhibitor treatment and can be used as a predictive marker to guide selection of therapy
An Activatable Cancer-Targeted Hydrogen Peroxide Probe for Photoacoustic and Fluorescence Imaging.
No full textReactive oxygen species play an important role in cancer, however, their promiscuous reactivity, low abundance, and short-lived nature limit our ability to study them in real time in living subjects with conventional noninvasive imaging methods. Photoacoustic imaging is an emerging modality for visualization of molecular processes with deep tissue penetration and high spatiotemporal resolution. Here, we describe the design and synthesis of a targeted, activatable probe for photoacoustic imaging, which is responsive to one of the major and abundant reactive oxygen species, hydrogen peroxide (HO). This bifunctional probe, which is also detectable with fluorescence imaging, is composed of a heptamethine carbocyanine dye scaffold for signal generation, a 2-deoxyglucose cancer localization moiety, and a boronic ester functionality that specifically detects and reacts to HO. The optical properties of the probe were characterized using absorption, fluorescence, and photoacoustic measurements; upon addition of pathophysiologic HO concentrations, a clear increase in fluorescence and red-shift of the absorption and photoacoustic spectra were observed. Studies performed showed no significant toxicity and specific uptake of the probe into the cytosol in breast cancer cell lines. Importantly, intravenous injection of the probe led to targeted uptake and accumulation in solid tumors, which enabled noninvasive photoacoustic and fluorescence imaging of HO. In conclusion, the reported probe shows promise for the visualization of hydrogen peroxide. SIGNIFICANCE: This study presents the first activatable and cancer-targeted hydrogen peroxide probe for photoacoustic molecular imaging, paving the way for visualization of hydrogen peroxide at high spatiotemporal resolution in living subjects. http://cancerres.aacrjournals.org/content/canres/79/20/5407/F1.large.jpg
Insights on Heterogeneous Bimetallic Micellar Nanocatalysis for Buchwald-Hartwig Aminations
No full textNanocatalyst for micellar Buchwald-Hartwig aminations is developed, thoroughly characterized, and applied on a variety of substrates. Catalyst is stable under ambient conditions for up to six months. Association of Pd with Cu and together with ligand and carbon surface is revealed by XAS analysis. Catalyst retained its activity after several recycles, and its structure remained intact as confirmed by 31P NMR spectroscopy. In addition to XAS analysis, a complete characterization of catalyst is performed by SEM, HRTEM, XPS, TGA, IR, and NMR analysis. Control NMR experiments revealed the binding of the ligand with both the Cu and Pd and all phosphine molecules are under the same environment. Proline-based amphiphile PS-750-M is critical for catalytic activity, and catalytic reactions require mild conditions in water as gross reaction medium. Reactions are highly reproducible at variable scales. Low E factor and robust recycling of catalysts, environmentally benign amphiphile, and water confirmed the green-ness of technology
A Systematic Cheminformatics Analysis of Functional Groups Occurring in Natural Products.
No full textThe two most striking features that discriminate natural products from synthetic molecules are their characteristic scaffolds and unique functional groups (FGs). In this study we systematically investigate the distribution of FGs in natural products from a cheminformatics perspective by comparing FG frequencies in natural products with those found in average synthetic molecules. We thereby aim for the identification of FGs that are characteristic for molecules produced by living organisms. In our analysis we also include information about the natural origins of the structures investigated, allowing us to link the occurrence of specific FGs to the individual producing species. Our findings have the potential for being applied in a medicinal chemistry context concerning the synthesis of natural product-like libraries and natural product-inspired fragment collections. The results may be used also to support compound derivatization strategies and the design of "non-natural" natural products
A systematic in vitro investigation of the inhibitor preincubation effect on multiple classes of uptake transporters
No full textPreincubation of a drug uptake transporter with its inhibitor in a cell-based assay may result in the
apparent enhancement of the inhibitory potency. Limited data is available on whether this
potentiation of transporter inhibition by preincubation (PTIP) takes place with clinically relevant
solute-carrier transporters other than OATP1B1/3. Therefore, PTIP was examined systematically
using OATP1B1/3, OAT1/3, OCT1/2, and MATE1/2-K cell lines. IC50 values were determined with
or without 3 hours of preincubation, and compounds with a PTIP ≥2.5x were further characterised
by assessing the time course of transport inhibition potency and cellular concentration. The extent
of potentiation was correlated with the physicochemical properties of individual inhibitors. PTIP
was observed for OCTs as well as OATPs but not for OATs or MATEs, and most instances of
PTIP persisted after controlling for toxicity and non-specific binding. In certain cases,
preincubation in excess of 2 hours was required to attain full inhibitory potency. For 5/30 drugs
examined, preincubation had the potential to change the in vitro drug-drug interaction risk
prediction from ‘no risk’ to ‘risk’ based on current regulatory criteria. Molecular weight and LogD7.4,
as well as the ratio of passive cellular accumulation and cellular uptake rate (Kp,passive/PSinf)
correlated with PTIP; thus, low cellular permeation and a slow build-up of unbound intracellular
inhibitor concentration may contribute to PTIP. Taken together, our data suggest that PTIP is
partly determined by the physicochemical properties of the perpetrator drug, and preincubation
may affect the in vitro predicted DDI risk for OCTs as well as OATPs
Green Chemistry Articles of Interest to the Pharmaceutical Industry
No full textThis is a 6 month review of the literature in the light of green chemistry
Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes
No full textHdm2 (human MDM2) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Here, we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds. We also reveal the key additive 18-crown-ether, which we have discovered to enable HdmX crystallization and show its stabilization of various Lys-residues. In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. An analysis of all compound binding modes reveals new and deepened insights into the possible adaptations and structural states of Hdm2 (e.g. flip of F55; flip of Y67; reorientation of H96) and HdmX (e.g. flip of H55; dimer induction), enabling key binding interactions for different compound classes. In order to make comparisons easier, we have used the same numbering for Hdm2 and HdmX. Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors
Enzymatic interconversion of the oxysterols 7β,25-dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2
No full textOxysterols are cholesterol metabolites derived through either autoxidation or enzymatic processes. They consist of a large family of bioactive lipids that have been associated with the progression of multiple pathologies. In order to unravel (patho-)physiological mechanisms involving oxysterols, it is crucial to elucidate the underlying formation and degradation of oxysterols. A role of 11β-hydroxysteroid dehydrogenases (11β-HSDs) in oxysterol metabolism by catalyzing the interconversion of 7-ketocholesterol (7kC) and 7β-hydroxycholesterol (7βOHC) has already been reported. The present study addresses a function of 11β-HSD1 in the enzymatic generation of 7β,25-dihydroxycholesterol (7β25OHC) from 7-keto,25-hydroxycholesterol (7k25OHC) and tested whether 11β-HSD2 is able to catalyze the reverse reaction. For the first time, using recombinant enzymes, the formation of 7k25OHC from 7kC by cholesterol 25-hydroxylase (CH25H) and further stereospecific oxoreduction to 7β25OHC by human and mouse 11β-HSD1 could be demonstrated. Additionally, experiments using human 11β-HSD2 showed the oxidation of 7β25OHC to 7k25OHC. Molecular modeling provided an explanation for the stereospecific interconversion of 7β25OHC and 7k25OHC. Production of the Epstein-Barr virus-induced gene 2 (EBI2) ligand 7β25OHC from 7k25OHC in challenged tissue by 11β-HSD1 may be important in inflammation. In conclusion, these results demonstrate a novel glucocorticoid-independent pre-receptor regulation mediated by 11β-HSDs
Postdoc program external website
No full textEdits to the Postdoc program pages on Novartis.com to include the new innovation fellowship trac
Alkaloids purified from the Aristotelia chilensis tree inhibit the human α3β4 nicotinic acetylcholine receptor with higher potency compared to human α4β2 and α7 subtypes
No full textThe alkaloids aristone, aristoteline, and aristoquinoline are purified from the leaves of the Maqui tree Aristotelia chilensis and chemically characterized by NMR spectroscopy. The pharmacological activity of these natural compounds is subsequently determined on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results establish that these alkaloids do not have agonistic, but inhibitory, activity on any receptor subtype. The obtained IC50 values indicate the following receptor selectivity: hα3β4 > hα4β2 >> hα7. In the particular case of hα3β4 AChRs, aristoteline (0.40 ± 0.20 µM) and aristoquinoline (0.96 ± 0.38 µM) show higher potencies compared to aristone (167 ± 3 µM). Molecular docking and structure-activity relationship results indicate that ligand lipophilicity is important for the interaction with the luminal site located close to the cytoplasmic side of the hα3β4 ion channel between positions 2' and -4'. Aristoteline could be used as a molecular scaffold for the development of more potent noncompetitive inhibitors with higher selectivity for the hα3β4 AChR that could serve for novel addiction and depression therapies