Potent and selective inhibitors of PI3Kδ: Obtaining isoform selectivity from the affinity pocket and tryptophan shelf

Sutherlin, Daniel P.; Baker, Stewart; Bisconte, Angelina; Blaney, Paul; Brown, Anthony; Chan, Bryan; Chantry, David; Castanedo, Georgette; Depledge, Paul; Goldsmith, Paul; Goldstein, David; Hancox, Timothy; Kaur, Jaspreet; Knowles, David B.; Kondru, Rama K.; Lesnick, John; Lucas, Matthew C.; Lewis, Cristina; Murray, J.M.; Nadin, Alan; Nonomiya, Jim; Pang, Jodie; Pegg, Neil; Price, Steve; Reif, Karin; Safina, Brian S.; Salphati, Laurent; Staben, Steven T.; Seward, Eileen M.; Shuttleworth, Stephen J.; Sohal, Sukhjit; Sweeney, Zachary K.; Ultsch, Mark; Waszkowycz, Bohdan; Wei, BinQing

doi:10.1016/j.bmcl.2012.05.027

Cited by 49 publications

(85 citation statements)

References 23 publications

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“…Meanwhile, no reversible or time‐dependent CYP inhibition was observed on 41 . Similar results were observed on compound 42 as well . Meanwhile, compound 42 was found significantly inhibited B‐cell activation at oral doses of as low as 1 mg/kg.…”

Section: Pi3kδ In Cll and The Development Of Pi3kδ Inhibitorssupporting

confidence: 83%

“…Similar results were observed on compound 42 as well. 78,79 Meanwhile, compound 42 was found significantly inhibited B-cell activation at oral doses of as low as 1 mg/kg.…”

Section: Thienpyrimidines and Derivativesmentioning

confidence: 98%

“…Encouraged by results of compound 39, the same research group conducted an additional SAR to identify new benzimidazole-containing PI3Kδ inhibitors with higher selectivity against other PI3K isoforms, especially PI3Kα. [75][76][77] Accordingly, a series of [5,6]-and [6,6]-bicycles 40 78,79 (thienopyrimidine, imidazolopyrimidine, thiazolopyrimidine, pyridopyrimidine) were tested as the central core ( Fig. 12).…”

Section: Thienpyrimidines and Derivativesmentioning

confidence: 99%

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Targeting PI3Kδ: Emerging Therapy for Chronic Lymphocytic Leukemia and Beyond

et al. 2015

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Chronic lymphocytic leukemia (CLL) remains the most incurable leukemia. Early chemotherapeutic treatments, including alkylating agents, purine nucleoside derivatives, and immunotherapeutic antibodies, only show limited benefits for patients but severe off-target related side effects. Recent advances in understanding of the critical molecular pathways of regulating proliferation and survival of B-CLL cells have spurred a new therapeutical strategy by selectively targeting phosphoinositide 3-kinase delta (PI3Kδ). Idelalisib, a first-in-class PI3Kδ-selective small molecule has received the FDA's fast-track approval in July of 2014 as a new treatment of CLL, indolent B-cell non-Hodgkin's lymphoma, and relapsed small lymphocytic lymphoma. Undoubtedly, the success of idelalisib has provided a solid support in the development of PI3Kδ-specific inhibitors and reformed the concept of treating CLL. However, the number of reported selective inhibitors of PI3Kδ is very limited and very few have advanced into clinical trials. The mechanism of their actions remains elusive. More profound understanding on the modes of action of new PI3Kδ inhibitors will further validate the PI3Kδ-targeting strategy, and help to identify biomarkers capable of stratifying patients who will most likely benefit from the therapy.

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Section: Pi3kδ In Cll and The Development Of Pi3kδ Inhibitorssupporting

confidence: 83%

“…Similar results were observed on compound 42 as well. 78,79 Meanwhile, compound 42 was found significantly inhibited B-cell activation at oral doses of as low as 1 mg/kg.…”

Section: Thienpyrimidines and Derivativesmentioning

confidence: 98%

Section: Thienpyrimidines and Derivativesmentioning

confidence: 99%

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Targeting PI3Kδ: Emerging Therapy for Chronic Lymphocytic Leukemia and Beyond

et al. 2015

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“…31 The core structure used here was a pyridopyrimidine ( 86 ) which was then substituted by an amine. The indole or benzimidazole (linked to the pyrimidine via carbon) was then added via its boronic acid or ester via a Suzuki coupling to produce 87 .…”

Section: Pyrimidines and Quinazolinesmentioning

confidence: 99%

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

Welker

Kulik

2013

Bioorganic & Medicinal Chemistry

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This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, i.e. inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.

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“…It is believed that the PI3K/AKT pathway is particularly pertinent for MM growth and therapy. There are four members in the Class I PI3K family, namely, PI3Kα, β, δ and γ, all of which are overactivated in MM cell lines and primary myeloma patient cells [17]. Moreover, phosphatase and tensin homolog (PTEN), the critical negative modulator of PI3K signaling, is frequently deleted or inactivated by mutation in MM cells [18].…”

Section: Introductionmentioning

confidence: 99%

Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization

Han

Chen

et al. 2014

J Hematol Oncol

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BackgroundWe previously reported a PI3K inhibitor S14161 which displays a promising preclinical activity against multiple myeloma (MM) and leukemia, but the chiral structure and poor solubility prevent its further application.MethodsSix S14161 analogs were designed based on the structure–activity relationship; activity of the compounds in terms of cell death and inhibition of PI3K were analyzed by flow cytometry and Western blotting, respectively; anti-myeloma activity in vivo was performed on two independent xenograft models.ResultsAmong the six analogs, BENC-511 was one of the most potent compounds which significantly inhibited PI3K activity and induced MM cell apoptosis. BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 μM but had no effects on their total protein expression. Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death, which further demonstrated that PI3K signaling pathway was critical for the anti-myeloma activity of BENC-511. Moreover, BENC-511 also showed potent oral activity against myeloma in vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models at a dose of 50 mg/kg body weight, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis.ConclusionsBecause of its potent anti-MM activity, low toxicity (LD50 oral >1.5 g/kg), and easy synthesis, BENC-511 could be developed as a promising agent for the treatment of MM via suppressing the PI3K/AKT signaling pathway.

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Potent and selective inhibitors of PI3Kδ: Obtaining isoform selectivity from the affinity pocket and tryptophan shelf

Cited by 49 publications

References 23 publications

Targeting PI3Kδ: Emerging Therapy for Chronic Lymphocytic Leukemia and Beyond

Targeting PI3Kδ: Emerging Therapy for Chronic Lymphocytic Leukemia and Beyond

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization

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