Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER + breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f ]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.
A total of 17 Nudix hydrolases were tested for their ability to hydrolyze 5-phosphoribosyl 1-pyrophosphate (PRPP). All 11 enzymes that were active toward dinucleoside polyphosphates with 4 or more phosphate groups as substrates were also able to hydrolyze PRPP, whereas the 6 that could not and that have coenzyme A, NDP-sugars, or pyridine nucleotides as preferred substrates did not degrade PRPP. The products of hydrolysis were ribose 1,5-bisphosphate and P i . Active PRPP pyrophosphatases included the diphosphoinositol polyphosphate phosphohydrolase (DIPP) subfamily of Nudix hydrolases, which also degrade the non-nucleotide diphosphoinositol polyphosphates. K m and k cat values for PRPP hydrolysis for the Deinococcus radiodurans DR2356 (di)nucleoside polyphosphate hydrolase, the human diadenosine tetraphosphate hydrolase, and human DIPP-1 (diadenosine hexaphosphate and diphosphoinositol polyphosphate hydrolase) were 1 mM and 1.5 s ؊1 , 0.13 mM and 0.057 s ؊1 , and 0.38 mM and 1.0 s ؊1 , respectively. Active site mutants of the Caenorhabditis elegans diadenosine tetraphosphate hydrolase had no activity, confirming that the same active site is responsible for nucleotide and PRPP hydrolysis. Comparison of the specificity constants for nucleotide, diphosphoinositol polyphosphate, and PRPP hydrolysis suggests that PRPP is a significant substrate for the D. radiodurans DR2356 enzyme and for the DIPP subfamily. In the latter case, generation of the glycolytic activator ribose 1,5-bisphosphate may be a new function for these enzymes.
Under-utilised orphan crops hold the key to diversified and climate-resilient food systems. Here, we report on orphan crop genomics using the case of Lablab purpureus (L.) Sweet (lablab) - a legume native to Africa and cultivated throughout the tropics for food and forage. Our Africa-led plant genome collaboration produces a high-quality chromosome-scale assembly of the lablab genome. Our assembly highlights the genome organisation of the trypsin inhibitor genes - an important anti-nutritional factor in lablab. We also re-sequence cultivated and wild lablab accessions from Africa confirming two domestication events. Finally, we examine the genetic and phenotypic diversity in a comprehensive lablab germplasm collection and identify genomic loci underlying variation of important agronomic traits in lablab. The genomic data generated here provide a valuable resource for lablab improvement. Our inclusive collaborative approach also presents an example that can be explored by other researchers sequencing indigenous crops, particularly from low and middle-income countries (LMIC).
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