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.
- Idelalisib (PI3K Delta inhibitor) FDA approved July 2014 for leukemia and two types of lymphoma.
- Perifosine, for colorectal cancer and multiple myeloma. (discontinued 2013)
- Idelalisib also for chronic lymphocytic leukaemia. Trials for CLL terminated/abandoned in 2015.
- Idelalisib for indolent non-Hodgkin lymphoma.
- 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.
- 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.
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)
- XL765 (also known as SAR245409)
- 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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- "FDA approves Zydelig for three types of blood cancers". US Food and Drug Administration. July 23, 2014.
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- Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016
- Clinical trial number NCT01068483 at ClinicalTrials.gov
- Clinical trial number NCT01132664 at ClinicalTrials.gov
- PI3K Inhibitor Penetrates Endocrine-Resistant Breast Cancer. Dec 2015
- "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". finanznachrichten.de. 31 October 2011.
- "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". Retrieved November 28, 2011.
- 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)
- "Evaluate the Safety and Efficacy of TGR 1202 in Patients With Relapsed or Refractory Hematologic Malignancies". clinicaltrials.gov.
- 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
- Bayer to Present New Data on Growing Oncology Pipeline. April 2013 Archived 2013-04-14 at the Wayback Machine.
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- PX-866 June 2010[permanent dead link]
- Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
- "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 Nov 2010.
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- Clinical trial number NCT00620594 for "A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer" at ClinicalTrials.gov
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- CUDC-907 Treatment in People With Metastatic and Locally Advanced Thyroid Cancer
- Business Wire. "Curis Presents Data On PI3K And HDAC Inhibitor CUDC-907 At The 2011 AACR-NCI-EORTC Symposium". TheStreet.
- Novel Dual HDAC/PI3K Inhibitor Assessed in Lymphoma, Myeloma. April 2016
- Dual HDAC, PI3K Inhibitor Active in Lymphoma, Myeloma. April 2016
- New PI3K Delta Inhibitor to Treat Blood Cancers Shows Promise in Early Clinical Study May 2, 2016. Ines Martins Archived May 6, 2016, at the Wayback Machine.
- Infinity Provides Company Update... May 2016
- IPI-549 early clinical. Sept 2016
- Definition of pan-PI3K/mTOR inhibitor SF1126 - National Cancer Institute Drug Dictionary. Cancer.gov. Retrieved on 2010-11-05.
- "Semafore's PI3 Kinase Inhibitor SF1126 Is A Vascular Targeted Conjugate In Phase I Clinical Trials In Solid Tumors And Multiple Myeloma" (Press release). Semafore Pharmaceuticals. April 15, 2008. Retrieved November 3, 2010.
- Clinical trial number NCT00907205 for "A Dose Escalation Study of SF1126, a PI3 Kinase (PI3K) Inhibitor, Given By Intravenous (IV) Infusion in Patients With Solid Tumors (SF112600106)" at ClinicalTrials.gov
- Semafore's SF1126 peptidic prodrug demonstrates clinical activity in chronic lymphocytic leukemia. News-medical.net. Retrieved on 2010-11-05.
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- Rhizen Pharmaceuticals SA. "Rhizen Pharmaceuticals S.A. announces initiation of a "First in Human" Phase-1 trial of RP6530, a dual PI3K delta/gamma inhibitor, in patients with hematological malignancies". GlobeNewswire News Room.
- "Intellikine commences INK1117 Phase I dose escalation study in cancer". 12 Oct 2011.
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- Clinical trial number NCT00876109 at ClinicalTrials.gov
- Clinical trial number NCT00876122 for "A Study of GDC-0941 in Patients With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma for Which Standard Therapy Either Does Not Exist or Has Proven Ineffective or Intolerable" at ClinicalTrials.gov
- Clinical trial number NCT01042925 at ClinicalTrials.gov
- Clinical trial number NCT00485719 at ClinicalTrials.gov
- Clinical trial number NCT01033721 at ClinicalTrials.gov
- "GSK Clinical Register: PIK111051". Archived from the original on 2012-07-12.
- A Safety Study of Oral ZSTK474 in Patients With Cancer
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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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