Identification of a Potent Phosphoinositide 3‐Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs

Pirali, Tracey; Ciraolo, Elisa; Aprile, Silvio; Massarotti, Alberto; Berndt, Alex; Griglio, Alessia; Serafini, M. Teresa; Mercalli, Valentina; Landoni, Clarissa; Campa, Carlo Cosimo; Margaria, Jean Piero; Silva, Rangel L.; Grosa, Giorgio; Sorba, Giovanni; Williams, Roger L.; Hirsch, Emilio; Tron, Gian Cesare

doi:10.1002/cmdc.201700340

Cited by 19 publications

(14 citation statements)

References 41 publications

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“…Peak plasma concentration 5 min after i.v. administration showed that CL27e was twice more abundant than CL27c (Supplementary Table 3 ), as previously shown 14 . After i.v.…”

Section: Resultssupporting

confidence: 85%

“…To circumvent this drawback, CL27c (Supplementary Fig. 1a ) (Patent: WO/2012/073184) was designed as a cell-permeable lipophilic ester prodrug 14 . This compound is inactive in PI3K enzymatic assay with purified proteins but, once inside the cytoplasm, is metabolized by unspecific esterases into CL27e (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This compound is inactive in PI3K enzymatic assay with purified proteins but, once inside the cytoplasm, is metabolized by unspecific esterases into CL27e (Supplementary Fig. 1a–c ), a potent pan-class I PI3K inhibitor, acting at nanomolar concentration 14 . To confirm PI3K-selective inhibition, CL27e was tested against 250 kinases.…”

Section: Resultsmentioning

confidence: 99%

“…A potential way to overcome side effects in pulmonary diseases, like severe asthma and IPF, is to avoid systemic absorption by the local delivery of inhaled active compounds. A prodrug pan-PI3K inhibitor like CL27c 14 could present an even safer profile but its in vivo efficacy has yet remained unaddressed. To explore the safety and efficacy of this strategy, CL27c was administered through the inhaled route in murine models of asthma, severe asthma and pulmonary fibrosis and found to be able to significantly reduce inflammation, improve lung function, and reduce bleomycin-induced lethality with negligible systemic toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis

et al. 2018

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PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.

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“…Peak plasma concentration 5 min after i.v. administration showed that CL27e was twice more abundant than CL27c (Supplementary Table 3 ), as previously shown 14 . After i.v.…”

Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis

et al. 2018

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“…Several PI3K inhibitors are currently being evaluated in clinical trials. Pan‐Class I‐PI3K inhibitors, which act by targeting all 4 class I PI3K isoforms, have shown modest clinical efficacy in clinical trials . The toxicities associated with pan‐PI3K inhibitors, such as buparlisib (BELLE‐2 and BELLE‐3 trials) and pictilisib (FERGI trial), limit the clinical utility of these agents.…”

Section: Introductionmentioning

confidence: 99%

Phase I study of alpelisib (BYL719), an α‐specific PI3K inhibitor, in Japanese patients with advanced solid tumors

et al. 2019

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This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.

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Mechanism of activation and the rewired network: New drug design concepts

Nussinov

Zhang

Maloney

et al. 2021

Medicinal Research Reviews

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Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same‐allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure‐based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor‐specific network, ushering innovative considerations in precision medicine.

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Identification of a Potent Phosphoinositide 3‐Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs

Cited by 19 publications

References 41 publications

Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis

Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis

Phase I study of alpelisib (BYL719), an α‐specific PI3K inhibitor, in Japanese patients with advanced solid tumors

Mechanism of activation and the rewired network: New drug design concepts

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