Thursday, May 21, 2015

Drugs in Clinical Pipeline: Gedatolisib

Gedatolisib [1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea] is an exceptionally potent, selective, ATP-competitive, and reversible dual Phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. It is administered intravenously.

Gedatolisib suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2+, PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nM of Gedatolisib PKI-587 at 4 hours.

In vitro, Gedatolisib potently inhibited class I PI3Ks (IC50 PI3K-α = 0.4 nM, PI3K-β = 60 nM, PI3K-γ = 60 nM), PI3K-α mutants (IC50 E545K = 0.6 nM, H1047R = 0.8 nM), and mTOR (IC50 = 10 nM). Gedatolisib inhibited growth of 50 diverse human tumor cell lines at IC50 values of less than 100 nM.

The activity of Gedatolisib is as follows:

IC50 (PI3K-α enzyme assay) = 0.4 nM
IC50 (PI3K-β enzyme assay) = 60 nM
IC50 (PI3K-γ enzyme assay) = 60 nM
IC50 (mTOR enzyme assay) = 10 nM

Common Name: Gedatolisib
Synonyms:  PKI-587; PF-05212384; PF05212384; PF 05212384; PF5212384
IUPAC Name: 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea
CAS Number: 1197160-78-3
Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; mTOR Inhibitor; Dual-Kinase Inhibitor
Indication: Various Cancers; Treatment of Solid Tumors
Development Stage: Phase I
Company: Pfizer

Class 1 phosphoinositide 3-kinases (PI3K) play a key role in the biology of human cancer. The gene encoding the PI3K-α isoform (PIK3CA) is amplified or mutated in a wide range of cancers. Aberrantly elevated PI3K/Akt/mTOR pathway signaling has been implicated in poor prognosis and survival in patients with lymphatic, breast, prostate, lung, glioblastoma, melanoma, colon, and ovarian cancers. In addition, PI3K/Akt/mTOR pathway activation contributes to resistance of cancer cells to both targeted anticancer therapies and conventional cytotoxic agents. An effective inhibitor of the PI3K/Akt/mTOR pathway could prevent cancer cell proliferation and induce programmed cell death [1].

Gedatolisib, a potent pan–class I phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, showed single-agent efficacy in multiple preclinical tumor models. Tumor regression was observed in several models. This effect was most pronounced against MDA-MB-361 (breast), which has elevated HER2 levels and mutant PI3K-α. Preclinical data suggest utility of PKI-587 in the treatment of cancers with elevated PI3K/mTOR signaling, including those resistant to agents that target HER2 or epidermal growth factor (EGF) receptors (EGFR).PKI-587 efficacy was enhanced when combined with a MEK1,2 kinase inhibitor (PD0325901), or irinotecan in a colon tumor model (HCT116) with mutant K-Ras. PKI-587 showed single-agent efficacy against a non–small cell lung cancer model (H1975) with mutant EGFR (L858R/T790M), and this activity was also enhanced when combined with the irreversible HER2 kinase inhibitor, HKI-272 [1].

Gedatolisib showed single-agent efficacy in both xenograft and orthotopic versions of the H1975 [NSCLC; EGFR (L858R/T790M)] model. In H1975 xenografts, continuous dosing of PKI-587 (at >5 mg/kg) caused early time point tumor regression. In the H1975 orthotopic model, 25 mg/kg PKI-587 (weekly) kept (9 of 10) treated mice alive, whereas all control mice (10 of 10) were dead by day 40. This suggests that PKI-587 could be used against lung tumors that have acquired resistance to EGFR inhibitors such as Iressa or Tarceva.

Phase I Study in Patients with Advanced Cancer

The part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation [3].

Methodology and Findings

Seventy-seven of the 78 enrolled patients received treatment. The MTD for Gedatolisib, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (greater than 6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for Gedatolisib (half-life, 30-37 hours after multiple dosing). Gedatolisib inhibited downstream effectors of the PI3K pathway in paired tumor biopsies.


Gedatolisib has potential to advance into further clinical development for patients with advanced solid malignancies.

1. Mallon, R.; et. al. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res 2011, 17(10), 3193-3203.
2. Venkatesan, A. M.; et. al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem 2010, 53(6), 2636-2645. (synthesis)
3. Shapiro, G. I.; et. al. First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin Cancer Res 2015, 21(8), 1888-1895.
4.  Study of PF-05212384 (Also Known as PKI-587) Administered Intravenously To Subjects With Solid Tumors (B2151001). NCT00940498 (retrieved 19-05-2015)
5. Investigation Of The Metabolism, And Excretion Of [14c]-PF-05212384 In Healthy Male Volunteers. NCT02142920 (retrieved 19-05-2015)
6. A Study Of PF-05212384 In Combination With Other Anti-Tumor Agents. NCT01920061 (retrieved 19-05-2015)