Table 1.
PI3K inhibitors are reported together with isoform selectivity, inhibitory constant 50 (IC50) expressed in nM and FDA approval label, whenever applicable in both solid tumours and haematological malignancies.
| Drug | Type | PIK3CA (IC50) | PIK3CB (IC50) | PIK3CD (IC50) | PIK3CG (IC50) | Specific mutations | FDA label | Indication in ongoing trials | NCT number | Experimental combinations |
|---|---|---|---|---|---|---|---|---|---|---|
| Buparlisib (NVP-BKM120) | Pan PI3K | 52 | 166 | 116 | 262 | No | No | HNSCC (III) | NCT04338399 | |
| Pictilisib GDC-0941) | Pan PI3K | 3 | 33 | 3 | 75 | No | No | |||
| Pilaralisib (XL147) | Pan PI3K | 39 | 36 | 36 | 23 | No | No | |||
| Sonolisib (PX-866) | Pan PI3K | 0.1 | >300 | 2.9 | 1 | No | No | |||
| Copanlisib (BAY 80-6946) | Pan PI3K | 0.5 | 3.7 | 0.7 | 6.6 | No | FL after 2 lines | HR + BC(I/II); HER2 + BC(I/II); TNBC(I/II); NSCLC (I); solid tumours (I); MSS colorectal cancer (I/II); castration-resistant prostate cancer (I/II); gynaecological–peritoneal (I/II); solid tumours (I/II); thyroid cancer radioiodine refractory (I) | NCT04895579; NCT03842228; NCT03711058; NCT04253262; NCT05010096; NCT04345913; NCT05082025; NCT03803761; NCT03586661; NCT04317105; NCT04462471; NCT03939897; NCT04108858; NCT02465060; NCT03878524 | Durvalumab; Olaparib + Durvalumab; Nivolumab; Nivolumab + Ipilimumab; Rucaparib; Elimusertib; Eribulin; Fulvestrant; Niraparib; Vemurafenib; Fulvestrant + Abemaciclib; Trastuzumab + Pertuzumab |
| Alpelisib (NVP-BYL719) | Selective (PIK3CA) | 4.6 | 1200 | 290 | 250 | No | PIK3Ca mutant HR+ and HER2– breast cancer | HR + BC (I/II/III); HER2 + BC (II/III); TNBC (I/II/III); colorectal cancer (I/II); HNSCC (I/II); gastric cancer (I/II); serous ovarian cancer (III); HPV-positive oropharingeal cancer (II); endometrial (I); meningioma (I) | NCT05143229; NCT04524000; NCT04208178; NCT04753203; NCT04216472; NCT03207529; NCT05038735; NCT04997902; NCT04729387; NCT04762979; NCT04526470; NCT04544189; NCT03631953; NCT03601507; NCT04251533; NCT05154487; NCT04862143; NCT05063786; NCT04943497; NCT03284957; NCT04188548 | Sacituzumab Govitecan; Fulvestrant; Trastuzumab + Pertuzumab; Capecitabine; Nab-paclitaxel; Enzalutamide; Tipifarnib; Olaparib; Aromatase inhibitor; Paclitaxel; Trametinib; Trastuzumab + Fulvestrant + /− Vinorelbine + /− Capecitabine + /− Eribulin; Ribociclib + Chemotherapy; Amcenestrant; LY3484356 |
| Taselisib (GDC-0032) | Dual (PI3K A + G) | 0.29 | 9.1 | 0.97 | 0.12 | No | No | Solid tumours (II) | NCT02465060 | |
| Inavolisib (GDC-0077/RG-6114) | Selective (PIK3CA) | 0.034 | 100 | 12 | 18 | No | No | HR + BC (I/II/III); HER2 + BC (I); colorectal cancer (I) | NCT04191499; NCT03006172; NCT04802759; NCT04589845 | Palbociclib + Fulvestrant; Letrozole; Letrozole + Palbociclib; Fulvestrant; Fulvestrant + Palbociclib; Fulvestrant + Palbociclib + Metformin; Trastuzumab + Pertuzumab; Bevacizumab; Giredestrant |
| Serabelisib (TAK-117/MLN1117/Petra 06) | Selective (PIK3CA) | 15 | 4500 | 1900 | 14,000 | No | No | |||
| MEN 1611 (CH5132799) | Selective (PIK3CA) | 14 | 120 | 500 | 36 | No | No | HR + HER2 + BC (I); colorectal (I/II) | NCT03767335; NCT04495621 | Trastuzumab + Fulvestrant; Cetuximab |
| CYH-33 | Selective (PIK3CA) | 5.9 | 600 | 79 | 225 | No | No | Solid tumours (I); ovarian cancer (II); HR + BC (I) | NCT04586335; NCT05043922; NCT04856371 | Olaparib, Fulvestrant; Fulvestrant + Palbociclib; Letrozole + Palbociclib |
| GSK2636771 | Selective (PIK3CB) | >5800 | 5.2 | 58 | >126,000 | No | No | Solid tumours (II) | NCT02465060 | |
| SAR260301 | Selective (PIK3CB) | 1500 | 23 | 470 | >10,000 | No | No | |||
| Eganelisib (IPI-549) | Selective (PIK3CG) | 3200 | 3500 | >8400 | 16 | No | No | TNBC(II); renal cell carcinoma (II) | NCT03961698 | Atezolizumab + Nab-paclitaxel; Atezolizumab + Bevacizumab |
| Duvelisib IPI-145 | Dual (PI3K GD) | 1600 | 85 | 2.5 | 27 | No | CLL after 2 lines; FL after 2 lines; small lymphocyte lymphoma after 2 lines | Melanoma (I/II); HNSCC(II) | NCT04688658; NCT05057247 | Nivolumab; Docetaxel |
| Tenalisib (RP6530) | Dual (PI3K GD) | >300 | >100 | 25 | 33 | No | No | ER + BC (II) | NCT05021900 | |
| AZD8154 | Dual (PI3K GD) | 60 | 1250 | 6 | 8 | No | No | |||
| AMG319 (ACP319) | Selective (PIK3CD) | 33,000 | 2700 | 18 | 850 | No | No | |||
| Idelalisib (CAL-101/GS-1001) | Selective (PIK3CD) | 820 | 570 | 2.5 | 89 | No | CLL relapsing; FL after 2 lines; small lymphocyte lymphoma after 2 lines | |||
| Umbralisib (TGR-1202) | Selective (PIK3CD) | >10,000 | >10,000 | 6.2 | 1400 | No | CLL relapsing; FL; MZL | |||
| Nemiralisib (GSK2269557) | Selective (PIK3CD) | 5000 | 1600 | 0.13 | 6300 | No | No | |||
| Leniolisib (CDZ173) | Selective (PIK3CD) | 240 | 420 | 11 | 2200 | No | No | |||
| Parsaclisib (INCB-50465) | Selective (PIK3CD) | >20,000 | >20,000 | 1.1 | >10,000 | No | No | |||
| Seletalisib (UCB-5857) | Selective (PIK3CD) | 3600 | 2100 | 12 | 280 | No | No | |||
| Zandelisib (PWT-143/ME-401) | Selective (PIK3CD) | 5000 | 210 | 5 | 2100 | No | No | |||
| IOA-244 | Selective (PIK3CD) | 19,000 | 2900 | 150 | >20,000 | No | No | Solid tumours (I) | NCT04328844 | Cisplatin + Pemetrexed |
| Linperlisib (YY-20394) | Selective (PIK3CD) | 1200 | 140 | 4.6 | 5200 | No | No | Thymic cancer (II) | NCT04975061 | |
| SHC014748 | Selective (PIK3CD) | 240 | 96 | 0.77 | 101 | No | No | |||
| LOXO-783 | Allosteric PIK3CA mutant selective | No | No | No | No | PIK3CA H1047R | No |
Breast cancer (I) solid tumours (I) |
NCT05307705 | Fulvestrant; Imlunestrant; Abemaciclib; Anastrozole; Exemestane; Letrozole; Paclitaxel |
| RLY-2608 | Allosteric PIK3CA mutant selective | No | No | No | No | PIK3CA E542K or E545K or H1047R | No |
Breast cancer (I) solid tumours (I) |
NCT05216432 | Fulvestrant |
| KA2237 | Undisclosed | No | No | No | No | Undisclosed | No | |||
| TQ-B3525 | Undisclosed | No | No | No | No | Undisclosed | No | Gynaecologic cancers (II); HR + BC(II) | NCT04836663; NCT04355520 | Fulvestrant |
| HMPL-689 | Undisclosed | No | No | No | No | Undisclosed | No | n |
Ongoing clinical trials are reported together with experimental indications and agents in experimental combination only in solid tumours that is the topic of this review. The Supplementary Material in the file “chemical_structure_preclinical_info” provides publicly available chemical structure and preclinical data of these inhibitors. We provided the PubChem URL and chemical structure of the PI3K inhibitors in a Supplementary document.
PI3K phosphatidylinositol 3-kinase, IC50 50% inhibitory concentration, NCT National Clinical Trial, FL follicular lymphoma, HNSCC head and neck squamous cell carcinoma, HR hormone receptor, BC breast cancer, TNBC triple-negative breast cancer, NSCLC non-small cell lung cancer, MSS microsatellite stable, HPV human papillomavirus, CLL chronic lymphocytic leukaemia, MZL marginal zone lymphoma.