Drugs in Clinical Pipeline: Omipalisib

Omipalisib [2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide] is a highly potent and selective inhibitor of class I Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR). 

SAR studies on GSK1059615 eventually led to the identification of Omipalisib, an extraordinarily potent inhibitor of PI3Kα (p110α/p85α) with low picomolar activity (PI3Kα IC₅₀ = 0.04 nM). In biochemical assays, Omipalisib is significantly more potent than GSK1059615 (PI3Kα IC₅₀ = 2 nM) and is the most potent PI3Kα inhibitor reported to date. Omipalisib  is being evaluated in a phase I, open-label, dose-escalation study in subjects with solid tumors or lymphoma.

Omipalisib is also a low picomolar inhibitor of the common activating mutants of p110α (E542K, E545K, and H1047R, K_i = 0.008, 0.008 and 0.009 nM) found in human cancer. Similar to the other reported PI3K inhibitors, Omipalisib is also active against the other class I PI3K isoforms (β, γ, and δ).

The activity of Omipalisib is as follows:

K_i (p110α) = 0.019 nM

K_i (p110β) = 0.13 nM

K_i (p110γ) = 0.024 nM

K_i (p110δ) = 0.06 nM

Common Name: Omipalisib

Synonyms:  GSK-2126458; GSK2126458; GSK 2126458

IUPAC Name: 2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide

CAS Number: 1086062-66-9

Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; PI3Kα Inhibitor, MTOR Inhibitor

Indication: Various Cancers; Solid Tumors

Development Stage: Phase I

Company: GlaxoSmithKline

The phosphoinositide 3-kinase (PI3K) signaling pathway is activated in a broad spectrum of human cancers. Activation of this pathway often occurs indirectly by the activation of receptor tyrosine kinases or the inactivation of the phosphotase and tensin homologue (PTEN) tumor suppressor. Direct activation of PI3K has been demonstrated with the discovery of several activating mutations in the PIK3CA gene itself, the gene that encodes the p110α catalytic subunit of PI3KR. Several of the mutations found in PIK3CA have been shown to increase the lipid kinase activity of PI3KR, induce activation of signaling pathways, and promote transformation of cells both in vitro and in vivo. Furthermore, the PI3K pathway is the most commonly mutated signaling pathway in human cancers. The PI3K family of enzymes is comprised of 15 lipid kinases with distinct substrate specificities, expression patterns, and modes of regulation. In particular, PI3KR has emerged as an attractive target for cancer therapeutics, and several PI3K inhibitors are currently under evaluation in human clinical trials.

Omipalisib shows excellent selectivity over protein kinases (greater than10,000-fold vs more than 240 kinases evaluated) with the notable exception of the class IV PI3K family. mTOR, a class IV PI3K protein kinase, is a central regulator of cell growth and exists in two functional complexes, mTORC1 and mTORC2. mTORC2 is proposed to regulate AKT S473 phosphorylation, and its inhibition is believed to augment the antiproliferative efficacy of a PI3K inhibitor by dual inhibition of the PI3K/AKT pathway. The kinase domain of mTOR is homologous to the p110α catalytic subunit of the class I PI3Ks, and Omipalisib is a potent inhibitor of both mTOR complexes with subnanomolar activity (K_i mTORC1, mTORC2 = 0.18, 0.3 nM). Omipalisib is also a potent inhibitor of the class IV PI3 kinase, DNA-PK (IC₅₀ = 0.28 nM).

Omipalisib induces a G1 cell cycle arrest and inhibits cell proliferation in a large panel of cell lines, including T47D and BT474 breast cancer lines. The PK profile of Omipalisib was studied in four preclinical species (mouse, rat, dog, and monkey). The compound showed low blood clearance and good oral bioavailability. In addition, Omipalisib had minimal potential to inhibit the human cytochrome P450 isoforms [1].

Omipalisib induced morphologic changes in four tumors (two invasive ductal carcinomas, one invasive lobular carcinoma, and one ovarian dysgerminoma), intracellular caspase-3 activity in three tumors (two invasive ductal carcinomas and one poorly differentiated signet ring adenocarcinoma of gastric origin), and immunohistochemical evidence of apoptosis in at least four tumors (three invasive ductal carcinomas and one adenocarcinoma of gastric origin). Two tumors (ovarian serous carcinoma and moderately differentiated adenocarcinoma of colorectal origin) demonstrated no treatment effect [2].

References:

1. Knight, S. D.; et. al. Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med Chem Lett 2010, 1(1), 39-43.
2. Albawardi, A.; et. al. Cancer Cell Int 2014, 14(1), 90.
3. ClinicalTrials.gov Dose-Escalation Study of GSK2126458 (FTIH). NCT00972686 (retrieved 05-05-2015)
4. ClinicalTrials.gov A Proof of Mechanism Study With GSK2126458 in Patients With Idiopathic Pulmonary Fibrosis (IPF). NCT01725139 (retrieved 05-05-2015)