| 1. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 2. |
- Gustafsson, Robert, et al.
(författare)
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Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
- 2017
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:4, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD(+) and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment.
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| 3. |
- Llona-Minguez, Sabin, et al.
(författare)
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Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:3, s. 1140-1148
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Tidskriftsartikel (refereegranskat)abstract
- The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell sternness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.
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| 4. |
- Llona-Minguez, Sabin, et al.
(författare)
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Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 1 : Triazoles, triazolopyrimidines, triazinoindoles, quinoline hydrazones and arylpiperazines
- 2017
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 27:16, s. 3897-3904
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Tidskriftsartikel (refereegranskat)abstract
- A high-throughput screening campaign using a commercial compound library (ChemBridge DiverSET) revealed diverse chemotypes as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). Triazole, triazolopyrimidine, triazinoindole, quinoline hydrazone and arylpiperazine hits were clustered, confirmed by IC50 determinations, and their preliminary structure-activity-relationships (SAR) and ligand efficiency scores are discussed in this letter.
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| 5. |
- Llona-Minguez, Sabin, et al.
(författare)
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Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 2 : Pyridone- and pyrimidinone-derived systems
- 2017
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 27:15, s. 3219-3225
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Tidskriftsartikel (refereegranskat)abstract
- Two screening campaigns using commercial (Chembridge DiverSET) and proprietary (Chemical Biology Consortium Sweden, CBCS) compound libraries, revealed a number of pyridone- and pyrimidinone-derived systems as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). In this letter, we present their preliminary structure-activity-relationships (SAR) and ligand efficiency scores (LE and LLE).
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| 6. |
- Llona-Minguez, Sabin, et al.
(författare)
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Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1
- 2017
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 60:5, s. 2148-2154
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Tidskriftsartikel (refereegranskat)abstract
- The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compounds 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit -to-lead development.
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| 7. |
- Llona-Minguez, Sabin, et al.
(författare)
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Novel spirocyclic systems via multicomponent aza-Diels-Alder reaction
- 2017
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 15:37, s. 7758-7764
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Tidskriftsartikel (refereegranskat)abstract
- Here we present a two-step diastereoselective methodology building on a multicomponent aza-Diels-Alder reaction. Using previously unexplored cyclic ketones, heterocyclic amines and cyclopentadiene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between drug-like molecules and natural products.
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| 8. |
- Llona-Minguez, Sabin, et al.
(författare)
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Structure-metabolism-relationships in the microsomal clearance of piperazin-1-ylpyridazines
- 2017
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 8:7, s. 1553-1560
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we provide insight into the metabolic profile of a series of piperazin-1-ylpyridazines suffering from rapid in vitro intrinsic clearance in a metabolic stability assay using liver microsomes (e.g. compound 1 MLM/HLM t(1/2) = 2/3 min). Aided by empirical metabolite identification and computational predictive models, we designed the structural modifications required to improve in vitro intrinsic clearance by more than 50-fold (e.g. compound 29 MLM/HLM t(1/2) = 113/105 min).
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| 9. |
- Llona-Minguez, Sabin, et al.
(författare)
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Vinylic MIDA Boronates : New Building Blocks for the Synthesis of Aza-Heterocycles
- 2015
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 21:20, s. 7394-7398
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Tidskriftsartikel (refereegranskat)abstract
- A two-step synthesis of structurally diverse pyrrole-containing bicyclic systems is reported. ortho-Nitro-haloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a metal-free nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex drug-like molecules. Interestingly, an ortho-nitro-allylarene derivative furnished a cyclic beta-aminophosphonate motif.
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| 10. |
- Odell, Luke R., et al.
(författare)
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Synthesis of Substituted Indazole Acetic Acids by N-N Bond Forming Reactions
- 2023
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Ingår i: European Journal of Organic Chemistry. - : Wiley-Blackwell. - 1434-193X .- 1099-0690. ; 26:29
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Tidskriftsartikel (refereegranskat)abstract
- Herein, we report on the discovery and development of novel cascade N-N bond forming reactions for the synthesis of rare indazole acetic acid scaffolds. This approach allows for convenient synthesis of three distinct indazole acetic acid derivatives (unsubstituted, hydroxy, and alkoxy) by heating 3-amino-3-(2-nitroaryl)propanoic acids with an appropriate nucleophile/solvent under basic conditions. The reaction tolerates a range of functional groups and electronic effects and, in total, 23 novel indazole acetic acids were synthesized and characterized. This work offers a valuable strategy for the synthesis of useful scaffolds for drug discovery programs.
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