A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor

Borsari, Chiara; Rageot, Denise; Dall’Asen, Alix; Bohnacker, Thomas; Melone, Anna; Sele, Alexander; Jackson, Eileen; Langlois, Jean‐Baptiste; Beaufils, Florent; Hebeisen, Paul; Fabbro, Doriano; Hillmann, Petra; Wymann, Matthias P.

doi:10.1021/acs.jmedchem.9b00972

Cited by 24 publications

(44 citation statements)

References 48 publications

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“…Hence, revisions of formulations or treatment regimen may also be refined to avoid toxicities while obtaining a more durable response. More highly selective mTOR inhibitors are also currently being developed to improve specificity and metabolic stability [286].…”

Section: Targeting Mtorc1 and Mtorc2 With Atp-competitive Mtor Kinasementioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

156

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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Section: Targeting Mtorc1 and Mtorc2 With Atp-competitive Mtor Kinasementioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

156

128

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“…Compound 21 showed an improved potency as compared to 20 , and optimized physicochemical properties [27] . For the ( R )‐configured tricyclic pyrimido‐pyrrolo‐oxazine scaffold, a ( S )‐3‐methylmorpholine slightly increased the potency and selectivity for mTOR as opposed to unsubstituted hinge region morpholines [28a] . The ( R )‐3‐ methylmorpholine yielded the best mTOR selectivity of this series of conformationally restricted molecules.…”

Section: Structural Analysis Of Torkimentioning

confidence: 98%

Chemical and Structural Strategies to Selectively Target mTOR Kinase

2021

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Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cancer and neurological disorder, which identifies mTOR inhibition as promising strategy for the treatment of a variety of human disorders. First-generation mTOR inhibitors include rapamycin and its analogues (rapalogs) which act as allosteric inhibitors of TORC1. Structurally unrelated, ATP-competitive inhibitors that directly target the mTOR catalytic site inhibit both TORC1 and TORC2. Here, we review investigations of chemical scaffolds explored for the development of highly selective ATP-competitive mTOR kinase inhibitors (TORKi). Extensive medicinal chemistry campaigns allowed to overcome challenges related to structural similarity between mTOR and the phosphoinositide 3-kinase (PI3K) family. A broad region of chemical space is covered by TORKi. Here, the investigation of chemical substitutions and physicochemical properties has shed light on the compounds' ability to cross the blood brain barrier (BBB). This work provides insights supporting the optimization of TORKi for the treatment of cancer and central nervous system disorders.

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“…The (R)-3-methylmorpholine has been previously reported as a crucial feature to achieve selectivity for mTOR kinase over PI3Ks. 12,14 The orientation of the amino group on the 1,3,4-thiadiazole in 4 and on thiazole in 6 resembles that of the 2-amino substituted pyrimidine (1), pyrazine (3) and pyridine (5, Fig. 2b for 3-4), leading to the establishment of an H-bond network with Asp2195 and Glu2190.…”

Section: Rsc Medicinal Chemistrymentioning

confidence: 99%

“…followed by acidic hydrolysis of the intermediary sulfaminic acid and base-mediated ring closure. 14 To introduce a 1,2,4-thiadiazole and a pyrazine, a tributyltin group was appended on 13 , followed by Stille coupling between 14 and halides ( Scheme 1a ). The Stille reaction of 3-bromo-5-chloro-1,2,4-thiadiazole was regioselective for C-5 coupling to give bromo derivative 15 .…”

Section: Study Design and Synthesismentioning

confidence: 99%

“… 13 A systematic structure–activity relationship (SAR) study pinpointed the pyrazine derivative 12b as potent inhibitor of mTOR kinase ( K i = 8.0 nM), showing a 212-fold selectivity over the structurally related PI3Kα (see Table 1 for chemical structure). 14 However, 12b displayed a limited ability to cross the BBB, preventing its application in the treatment of CNS disorders such as epilepsy. Given the unexplored activity of the tricyclic pyrimido-pyrrolo-oxazine compounds in CNS indications, we selected this privileged scaffold as starting point for the development of novel lead compounds with potential brain permeability.…”

Section: Introductionmentioning

confidence: 99%

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