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The prenyl-binding protein PDEδ is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEδ, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEδ with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEδ inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEδ knockdown in a set of human pancreatic cancer cell lines. PDEδ is a widely expressed factor that sustains the spatial organization and signalling of Ras family proteins. Here the authors describe the activity of Deltazinone 1, a new highly selective PDEδ inhibitor of KRAS-dependent cancer cell growth with low cytotoxic side effects.

The sesquiterpene (−)Englerin A (EA) is an organic compound from the plant Phyllanthus engleri which acts via heteromeric TRPC4/C1 channels to cause cytotoxicity in some types of cancer cell but not normal cells. Here we identified selective cytotoxicity of EA in human synovial sarcoma cells (SW982 cells) and investigated the mechanism. EA induced cation channel current (Icat) in SW982 cells with biophysical characteristics of heteromeric TRPC4/C1 channels. Inhibitors of homomeric TRPC4 channels were weak inhibitors of the Icat and EA-induced cytotoxicity whereas a potent inhibitor of TRPC4/C1 channels (Pico145) strongly inhibited Icat and cytotoxicity. Depletion of TRPC1 converted Icat into a current with biophysical and pharmacological properties of homomeric TRPC4 channels and depletion of TRPC1 or TRPC4 suppressed the cytotoxicity of EA. A Na + /K + -ATPase inhibitor (ouabain) potentiated EA-induced cytotoxicity and direct Na + loading by gramicidin-A caused Pico145-resistant cytotoxicity in the absence of EA. We conclude that EA has a potent cytotoxic effect on human synovial sarcoma cells which is mediated by heteromeric TRPC4/C1 channels and Na + loading.

The ups and downs of a multi-year medicinal chemistry optimisation effort in the quest of identifying inhibitors of human steroid sulfatase as potential topical therapeutics are summarised. The focus lies on dead ends, redirection and mastering of the hurdles rather than detailed structure–activity relationship results of a series. In addition to the usual multi-parameter optimisation towards drug-like properties, unexpected barriers prohibitive for the planned clinical application had to be overcome. While a substrate- and mechanism-based design approach rapidly yielded aryl sulfamates as potent, irreversible enzyme inhibitors, this inhibitor class had to be abandoned due to inherent chemical instability in solution. The rescue of the project was a hit class from a random screening approach, but from there it still took quite some efforts to invent potent reversible inhibitors appropriate for development towards a clinical candidate. Graphical abstract

Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system 1 – 6 . The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS 7 – 17 , and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease. Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.

The prenyl-binding protein PDEδ is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEδ, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEδ with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEδ inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEδ knockdown in a set of human pancreatic cancer cell lines.

Untreated popliteal aneurysm (PA) may cause serious complications. Early detection and surgery are beneficial. What are the circumstances under which the diagnosis of PA is made? What risks are associated with the treatment? A total of 36 consecutive PAs in 22 men and 2 women were treated in a single‐center series. Altogether, 26 surgical reconstructions (group 1) were performed using a medial approach, and two PAs were resected through a dorsal approach. Eight patients with eight PAs did not undergo surgery (group 2): Two were awaiting surgery, and six had refused it. At the time of diagnosis, 25 PAs were symptomatic: local pain, swelling, or ”pulsation” in the popliteal groove (29%); claudication of the foot/calf (39%); critical ischemia (21%). Eleven asymptomatic cases were discovered during screening duplex sonography of known aortic aneurysms Among the 28 PAs that underwent surgery, 6 produced acute symptoms. The following complications were observed: five postoperative hematomas, one infected polytetrafluoroethylene (PTFE) graft, two early graft occlusions, and two significant stenoses of the distal anastomosis. After a mean follow‐up of 15 months (range 2‐43 months), group 1 had a limb salvage rate of 100% and a secondary patency rate of 96%. Two patients are still awaiting surgery. Critical ischemia represents an absolute indication for surgical repair, but the observed zero mortality and relatively low morbidity associated with the intervention combined with a favorable patency rate justify the liberal use of surgery even for asymptomatic PAs. The extensible medial approach is preferred. Sequential reconstruction is advised for bilateral PAs.

Readily available bicyclic enone precursors were used in a novel strategy for the synthesis of 6-mono- and 5,6-disubstituted tetrahydroisoquinolines (alkyl and phenyl in position 6, hydrogen and methyl in position 5). After 1,2-addition of the respective organometallic reagents to the enones, the crude intermediate alcohols were subjected to a dehydratization/aromatization procedure using the in situ generated triphenylmethyl cation. Overall yields obtained by this procedure were between 27 and 86%. Whereas the synthesis of N-benzyl protected 6-t-butyl-tetrahydroisoquinoline was successful, partial dealkylation occurred in the 5-methyl-6-t-butyl analogue. Some of the new N-benzyl tetrahydroisoquinolines were transformed into the corresponding unprotected heterocycles.

Overcoming drug-resistance and the subsequent relapse that often occurs with monotherapy is crucial in the treatment of acute myeloid leukemia. We here demonstrate that therapy-resistant leukemia initiating cells can be targeted using a novel inhibitor of mitochondrial transcription (IMT). The compound inhibits mitochondrial RNA polymerase activity and sensitizes the resistant population to the induction of apoptosis. In vitro studies on acute myeloid leukemia cells demonstrate that IMT prevents cell proliferation, and together with a selective BCL-2 inhibitor, venetoclax, induces apoptosis and suppress oxidative phosphorylation (OXPHOS) synergistically. AML mouse models treated with IMT in combination with venetoclax show prolonged survival in venetoclax-resistant models. Our findings suggest that certain therapy-resistant leukemia cell populations display a unique dependency on mitochondrial transcription and can be targeted with IMT.Competing Interest StatementCMG is a scientific co-founder of Pretzel Therapeutics Inc. Together with RD, TB, AU, PN, BMK who are employees of LDC, CMG is also co-inventor of the patent application WO 2019/057821. Medicinal chemistry and pharmacology part of this work was financed by the Max-Planck Gesellschaft e.V. under the framework agreement between Max-Planck and LDC.Footnotes* Update of text and revision of figures.

Aim Historical bird atlases provide comprehensive datasets for investigating long‐term changes in species' distribution. In the context of accelerating biodiversity loss, these datasets can lend critical insights into the state of bird distributions across broad spatio‐temporal scales and provide much‐needed information for impactful conservation. In Africa, the potential of atlas data to understand changes in avian populations remains largely untapped. Location This study mapped changes in national distribution patterns of 1088 bird species found in Kenya. Methods Tapping into one of the earliest atlas databases, this study compared Kenyan bird atlas data collected between 1970 and 1984 with recent citizen science data sourced from the Kenya Bird Map project and eBird to determine changes in ranges across 50 years. We produced maps displaying, for every 27 × 27 km square of the country, whether a species appeared, was present throughout both periods, or disappeared. We account for the change in data collection effort between the two periods by quantifying the confidence of the change for each square. Results The maps produced for each species are publicly accessible through an interactive website: https://kenyabirdtrends.co.ke/. We found that related species tended to experience similar changes in their distribution ranges. The ranges of Palearctic migrants and scavengers declined drastically, while introduced birds experienced a significant range increase over the past 50 years. Main Conclusions This study demonstrates the potential of integrating recent citizen science data with historical atlas data to draw out the changes in range for all species at national level. The range contraction of Palearctic migrants and scavengers echoed corresponding drops in abundance at local, regional and global scales. These findings lend additional weight to the need for an increased conservation focus on migratory and scavenging birds in Kenya.