Phosphoinositide 3-kinase inhibitor
A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a class of medical drug that functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signalling pathway for many cellular functions such as growth control, metabolism and translation initiation. Within this pathway there are many components, inhibition of which may result in tumor suppression. These anti-cancer drugs are examples of targeted therapy.
There are a number of different classes and isoforms of PI3Ks. Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha, p110 beta, p110 gamma and p110 delta. The inhibitors being studied inhibit one or more isoforms of the class I PI3Ks.
Effects of inhibiting different isoforms
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- Wortmannin: an irreversible inhibitor of PI3K.
- demethoxyviridin: a derivative of wortmannin.
- LY294002: a reversible inhibitor of PI3K.
- hibiscone C: an irreversible inhibitor of PI3K.
- Duvelisib: inhibitor of PI3K
- Idelalisib (PI3K Delta inhibitor) FDA approved July 2014 for leukemia and two types of lymphoma.
- Copanlisib (Inhibitor of PI3K, predominantly against PI3K-α and PI3K-δ) FDA approved in September 2017 for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.
- Duvelisib (First approved oral dual inhibitor of PI3K-delta and PI3K-gamma) The U.S. Food and Drug Administration (FDA) has approved Duvelisib by the name of COPIKTRA™ on September 24, 2018. COPIKTRA™ is the first approved dual inhibitor of PI3K-delta and PI3K-gamma. COPIKTRA is approved for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies.
- Taselisib, has potential selectivity for the PI3Kα isoform.1,2. In trials for breast cancer and lung cancer.
- Perifosine, for colorectal cancer and multiple myeloma. (discontinued 2013)
- Idelalisib also for chronic lymphocytic leukaemia. Trials for CLL terminated/abandoned in 2015.
- Idelalisib for follicular lymphoma. A dose optimization study
- Buparlisib (BKM120) for HR+/HER2 advanced endocrine-resistant breast cancer – encouraging results in Dec 2015.
- Duvelisib, (IPI-145) a novel inhibitor of PI3K delta and gamma, especially for hematologic malignancies and inflammatory conditions. It has started 4 phase 3 trials but in Nov 2016 Infinity exclusively licensed it to Verastem.
- Alpelisib (BYL719), an alpha-specific PI3K inhibitor, starting SOLAR-1 trial for PIK3CA-altered metastatic breast cancer. Trial to end July 2019. Some SOLAR-1 results announced Oct 2018.
- Umbralisib, (TGR 1202), oral PI3K delta inhibitor (previously known as RP5264). "has shown promising efficacy with a superior toxicity profile compared with idelalisib" Now in ph3 for CLL. 3 year data (inc Follicular Lymphoma and DLBCL) announced June 2016. Once daily administration. Named Umbralisib, and in combination trials for various lymphomas.
- Copanlisib (BAY 80-6946), predominantly inhibits PI3Kα,δ isoforms. for indolent non-Hodgkin lymphoma.
In/starting phase II clinical trials:
- PX-866 In 2010 Starting 4 phase II trials for solid tumours. Mixed results since 2012.
- Dactolisib The first into clinical trials, in 2006. A PI3K/mTOR dual inhibitor.
- CUDC-907, Also an HDAC inhibitor. In phase 2 clinical trial for advanced thyroid cancer.
- Voxtalisib (SAR245409, XL765), an inhibitor of 4 PI3K isoforms (p110α, p110β, p110γ, and p110δ) and a weaker inhibitor of mTOR. In trial for B-cell lymphomas, e.g. CLL and follicular lymphoma.
With phase I results announced :
- CUDC-907, Also an HDAC inhibitor. In 2016 it was reported as showing promising preliminary evidence of response in patients with diffuse large B-cell lymphoma. In phase 2 clinical trial for advanced thyroid cancer.
- ME-401, PI3K-delta Inhibitor.
- IPI-549, a PI3K-gamma inhibitor, in phase 1 for various cancers. Phase I results announced Sept 2016.
- SF1126 Some early clinical data has been presented. First PI3KI 'Orphan Drug' for B-cell chronic lymphocytic leukemia (CLL). SF1126 is the first PI-3 kinase inhibitor to enter pediatric cancer clinical trials via the NANT consortium.
In early stage clinical trials
- RP6530, Dual PI3K delta/gamma inhibitor for lymphomas.
- INK1117, a PI3K-alpha inhibitor in phase I.
- pictilisib (GDC-0941) IC50 of 3nM.
- XL147 (also known as SAR245408)
- Palomid 529
- GSK1059615 The phase I trial of this drug was terminated due to lack of sufficient exposure following single- and repeat- dosing.
- ZSTK474, a potent inhibitor against p110a.
- PWT33597, a dual PI3K-alpha/mTOR inhibitor – for advanced solid tumors. IND mid 2011. Phase I recruiting.
- IC87114 a selective inhibitor of p110δ. It has an IC50 of 100 nM for inhibition of p110-δ.
- TG100–115, inhibits all four isoforms but has a 5–10 fold better potency against p110-γ and p110-δ.
- RP6503, Dual PI3K delta/gamma inhibitor for the treatment of Asthma and COPD (Late pre-clinical stage).
- PI-103 Dual PI3K-mTOR inhibitor.
- GNE-477 is PI3K-alpha and mTOR inhibitor with IC50 values of 4nM and 21nM.
- AEZS-136, also inhibits Erk1/2.
- PI3K/AKT/mTOR pathway for inhibitors of AKT and mTOR downstream from PI3K
- P110δ#Pharmacology, P110δ (PI3K-delta) as a drug target
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- Novel Agents Show Promise Against Endocrine-resistant Breast Cancer. July 2016
- Alpelisib Combo Promising in PIK3CA-Altered, Heavily Pretreated Breast Cancer. March 2016
- Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment. (SOLAR-1)
- Novartis investigational BYL719 (alpelisib) plus fulvestrant nearly doubles median PFS in patients with PIK3CA mutated HR+/HER2- advanced breast cancer compared to fulvestrant alone Oct 2018
- "Evaluate the Safety and Efficacy of TGR 1202 in Patients With Relapsed or Refractory Hematologic Malignancies". clinicaltrials.gov.
- Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016
- Therapy Focus – TG Could Benefit From Zydelig Setback. March 2016
- TG Therapeutics Inc.: TG Therapeutics, Inc. Announces First Patient Enrolled in the Registration-Directed UNITY-DLBCL Phase 2b Trial. June 2016
- Follow-Up Data for Combination of TGR-1202 (umbralisib) plus Ibrutinib in Patients with Relapsed or Refractory CLL and MCL. 2017
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- CUDC-907 Treatment in People With Metastatic and Locally Advanced Thyroid Cancer
- Voxtalisib for CLL and B-Cell Lymphomas March 2018
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- Study to Investigate Effects of CAL-263 in Subjects With Allergic Rhinitis Exposed to Allergen in an Environmental Chamber
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