Pilaralisib (XL147, SAR245408) is a potent and highly selective inhibitor of class I phosphatidylinositol 3-kinase (PI3K) (α, β, γ, and δ). In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Pilaralisib, was being developed by Exelixis and its licensee, Sanofi (formerly sanofi-aventis), for the treatment of solid tumours. However, the product was not listed on Sanofi's early stage pipeline as of end of July 2015 and there have been no recent reports on development identified.

PIK-93 is the two most potent and multitargeted synthetic PI3-K inhibitors that have been reported. PIK-93 inhibits PI3Kγ and PI4KIIIβ, with IC50 values of 16 nM and 19 nM, respectively. PIK-93 also inhibits other members of PI3Ks, including PI3Kα, β, and δ, with IC50 values of 39 nM, 0.59 uM, and 0.12 uM, respectively. PIK-93 shows no obvious inhibitory effect against a panel of other kinases, even at a concentration of 10 uM. PIK-93 was identified as a potent anti-enterovirus compound. PIK-93 targeted PI4Kβ to inhibit interaction of viral 3D polymerase and phosphatidylinositol 4-phosphate on the reorganized membrane vesicle for viral replication complex formation. PIK-93 may provide a basis for the design of new classes of therapeutics against viral RNA replication.

AS-605240 is a potent and selective phosphoinositide 3-kinase (PI3K) gamma inhibitor. It selectively inhibits PI3Kgamma enzymatic activity as well as PI3Kgamma-mediated signaling and chemotaxis in vitro and in vivo. It also has peripheral activity versus other PI3K isoforms. AS-605240 did not progress to clinical development although it had been described as a development candidate.

PF-04979064 is a highly potent and orally bioavailable PI3K/mTOR dual inhibitor developed through structure-based drug design. It inhibited mTOR, PI3Kα, β, δ and γ isoforms and AKT phosphorylation with IC50 as 2.64 nM, 0.395 nM, 0.111 nM, 0.122 nM and 28.3 nM, respectively. PF-04979064 exhibited cellular potency with an IC50 of 9.1 nM in a BT20 cell assay. PF-04979064 exhibited excellent in vitro potency, very good solubility, high LipE, excellent kinome selectivity, robust PK/PD correlation and tumor growth inhibition (TGI) in a U87MG mouse xenograft model, and acceptable predicted human clearance after incorporating both CYP- and AO-mediated metabolism. PF-04979064 is the back-up candidate to PF-04691502 which is in Phase I/II clinical trials for treating solid tumors.

PKI-402 is a reversible, ATP-competitive, and equipotent inhibitor of class I PI3Ks, including the E545K and H1047R PI3K-α mutants, and mTOR (IC50 versus PI3K-α = 2 nmol/L). Selectivity of PKI-402 was established in a screen against 236 diverse human kinases. PKI-402 caused in vitro growth inhibition of human tumor cell lines derived from a diverse set of human tumor tissues, including breast, brain (glioma), pancreas, and non–small cell lung cancer (NSCLC) tissues. In vivo, PKI-402 displayed antitumor activity (i.v. route) in breast [MDA-MB-361: Her2+ and PIK3- CA (E545K)], glioma (U87MG and PTEN), and NSCLC (A549; K-Ras and STK11) xenograft models. PKI-402 may be useful either as a single agent or in combination with cytostatic or cytotoxic (e.g., temozolomide) drugs in treatment of glioblastoma multiforme.

IC87114 is a PI3K-delta-specific inhibitor, which inhibits PI3K-delta 58-fold more potently than PI3K-gamma, and over 100-fold more potently than PI3K-alpha and PI3K-beta. Pharmacological investigations on IC87114 originally focused on its effect against inflammation and autoimmune diseases. IC87114 treatment dramatically blocked amphetamine-induced hyperlocomotion, suggestive of antipsychotic potential. In addition, IC87114 exhibited promising therapeutic effect in a murine asthma model.

Wortmannin is a fungal metabolite that so far has been shown to act as a selective inhibitor of phosphoinositide 3-kinase. Wortmannin inhibits cancer cell growth and has shown activity against mouse and human tumor xenografts in mice. Wortmannin is the first described PI3K inhibitor with IC50 of 3 nM in a cell-free assay, with little selectivity within the PI3K family. Also blocks autophagosome formation and potently inhibits DNA-PK/ATM with IC50 of 16 nM and 150 nM in cell-free assays.

BAG-956 is a dual PDK1 and class I PI 3-kinase inhibitor (IC50 values are 245, 56, 446, 35 and 117 nM for PDK1 and PI3K p110 -α, -β, -δ, and -γ respectively). BAG-956 has been shown to inhibit cellular AKT phosphorylation at Thr308. BAG-956 also blocks cell proliferation and causes arrest in the G1 phase of the cell cycle. BAG-956 has been shown to slow tumor progression in mouse xenograft models.