Duvelisib: A 2018 Novel FDA-Approved Small Molecule Inhibiting Phosphoinositide 3-Kinases

Rodrigues, Daniel Alencar; Sagrillo, Fernanda S.; Fraga, Carlos A.M.

doi:10.3390/ph12020069

Cited by 58 publications

(34 citation statements)

References 26 publications

(43 reference statements)

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“…Growing evidence signposts PI3K as a druggable target for AML; indeed, there has been very productive development of small-molecule inhibitors targeting the PI3K/Akt/mTOR pathway. While PI3K/Akt/mTOR inhibitors have been effective treating other hematological malignancies, such as chronic lymphoblastic leukemia (CLL) and follicular lymphoma (FL), in AML, the clinical potential of PI3K/Akt/mTOR inhibitors has not yet been fully elucidated [29][30][31]. Clinical studies using PI3K/Akt/mTOR inhibitors as monotherapy have shown limited therapeutic efficacy, likely due to compensatory activation of other survival pathways [32].…”

Section: Introductionmentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.

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Section: Introductionmentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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“…However, this treatment frequently induced adverse effects [106]. Duvelisib, an inhibitor of PI3K-δ and PI3K-γ approved in 2018 for the treatment of relapsed/refractory CLL and small lymphocytic lymphoma (SLL) [107], was designed to affect the TME. Unfortunately, duvelisib showed serious side effects and it is only administered to patients who did not achieve a satisfactory response after at least two systemic therapies [108].…”

Section: Phosphoinositide 3-kinase Inhibitors (Pi3ki)mentioning

confidence: 99%

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

Pepe

Balatti

2020

JCM

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In the past decade, novel targeted therapy approaches, such as BTK inhibitors and Bcl2 blockers, and innovative treatments that regulate the immune response against cancer cells, such as monoclonal antibodies, CAR-T cell therapy, and immunomodulatory molecules, have been established to provide support for the treatment of patients. However, drug resistance development and relapse are still major challenges in CLL treatment. Several studies revealed that non-coding RNAs have a main role in the development and progression of CLL. Specifically, microRNAs (miRs) and tRNA-derived small-RNAs (tsRNAs) were shown to be outstanding biomarkers that can be used to diagnose and monitor the disease and to possibly anticipate drug resistance and relapse, thus supporting physicians in the selection of treatment regimens tailored to the patient needs. In this review, we will summarize the most recent discoveries in the field of targeted therapy and immunotherapy for CLL and discuss the role of ncRNAs in the development of novel drugs and combination regimens for CLL patients.

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“…It is soluble in ethanol and practically insoluble in water. Duvelisib was given orally 25 mg twice daily with or without food [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Analytical Quality by Design Approach in Rp-HPLC Method Development and Validation for the Estimation of Duvelisib

Ch¹,

Annapurna²,

Ks³

et al. 2021

Asian J Pharm Clin Res

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Objective: A simple, accurate, and robust RP-HPLC method was developed and validated for the estimation of Duvelisib using analytical quality by design approach. Methods: The critical method parameters (CMP) were systematically optimized using box-Behnken design (BBD). The CMP’s selected were % organic phase composition, column temperature, and flow rate. The critical quality attributes investigated were retention time and theoretical plates. Results: Chromatographic separation was accomplished on Agilent Zorbax Eclipse C18 (150×4.6 mm, 5 μm) column. The optimized and predicted data from Design Expert software consist of mobile phase 0.1 % orthophosphoric acid (46.3%): Acetonitrile (53.7%), pumped at a flow rate of 0.91 ml/min at 32.6°C gave the highest desirability function of 1. The retention time of the drug was found to be 2.85 min. The developed method was validated as per the ICH Q2 (R1) guidelines. Conclusion: Based on the analysis of variance values, the selected models were found to be significant with p<0.05. The results of the validation parameters were within the acceptable limit. The stability of the drug was examined under different stress conditions forcibly and significant degradation was found in acidic condition.

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Duvelisib: A 2018 Novel FDA-Approved Small Molecule Inhibiting Phosphoinositide 3-Kinases

Cited by 58 publications

References 26 publications

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

Analytical Quality by Design Approach in Rp-HPLC Method Development and Validation for the Estimation of Duvelisib

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