Monday, August 3, 2015

Drugs in Clinical Pipeline: Buparlisib

Buparlisib [5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine] is an orally available pan-class I Phosphoinositide-3-kinase (PI3K) inhibitor. It does not significantly inhibit mTOR and is highly selective against other protein or lipid kinases. Buparlisib was identified upon optimization of drug-like and in vivo protein kinase properties from a 2-morpholino-6-aminopyridyl-pyrimidine scaffold [1].

Buparlisib is approximately equipotent against the class IA PI3Ks α, β, and δ (IC50 = 52, 166 and 116 nM, respectively) and modestly less potent against the class IB γ isoform (IC50 = 262 nM). The compound also shows comparable potency against activating p110α somatic mutations (IC50 H1047R, E545K = 58 ± 2, 99 ± 6 nM, respectively) that have been described in a wide array of human cancers [1, 2].  

Buparlisib is significantly less potent in biochemical assays against the PI3K class III family member Vps34 (IC50 = 2410 ± 150 nM), the related class IV PIKK protein kinases mTOR, ATR, (IC50 = 2866 ± 1671, 8091 ± 2038 nM) and DNA-PK (IC50 greater than 10), and the distinct lipid kinase PI4Kβ (IC50 greater than 25) [1, 2]. 

Buparlisib was shown to be mostly inactive against all the kinases tested in an in-house selectivity panel with the exception of colony-stimulating factor 1 receptor (CSF1R, IC50 = 582 nM). This inhibitory activity was confirmed at a concentration of 5 µM in the Invitrogen functional kinase panel but no effect was observed in a cell-based CSF1R autophosphorylation assay. Buparlisib was further profiled in the Ambit kinase competition panel, in which EphA2 and fibroblast growth factor receptor 2 (FGFR2) kinases were found to be inhibited by more than 90% at a concentration of 1 µM.

The pharmacological, biologic, and preclinical safety profile of Buparlisib supports its clinical development and the compound is undergoing phase II clinical trials in patients with cancer.

The activity of Buparlisib is as follows:

IC50 (PI3Kα Filter binding assay; Kinase-Glo assay) = 52 ± 37 nM; 0.035 ± 0.017 uM
IC50 (PI3Kβ Filter binding assay; Kinase-Glo assay) = 166 ± 29 nM; 0.175 ± 0.067 uM
IC50 (PI3Kδ Filter binding assay; Kinase-Glo assay) = 116 nM; 0.108 ± 0.048 uM
IC50 (PI3Kγ Filter binding assay; Kinase-Glo assay) = 262 ± 94 nM; 0.348 ± 0.013 uM

Common Name: Buparlisib
Synonyms:  NVP-BKM120; NVP BKM120; BKM120; BKM 120
IUPAC Name: 5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine
CAS Number: 944396-07-0
Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor
Indication: Various Cancers
Development Stage: Phase II
Company: Novartis

The phosphoinositide-3-kinase (PI3K) family of lipid kinases is involved in a diverse set of cellular functions, including cell growth, proliferation, motility, differentiation, glucose transport, survival, etc. PI3K’s can be categorized into class I, II, or III, depending on their subunit structure, regulation, and substrate selectivity. Class IA PI3K’s are activated by receptor tyrosine kinases and consist of a regulatory subunit (p85) and a catalytic subunit (p110). There are three catalytic isoforms: p110α, β, and δ. A single class IB PI3K, activated by GPCRs, consists of only one member: a p110γ catalytic subunit and a p101 regulatory subunit. The primary in vivo substrate of the class I PI3K’s is phosphatidylinositol (4,5) diphosphate (PtdIns(4,5)P2), which upon phosphorylation at the 3-position of the inositol ring to form phosphatidylinositol triphosphate (3,4,5)P3 (PIP3) serves as a second messenger by activating a series of downstream effectors that mediate the cellular functions mentioned above. The PI3K isoforms have different distributions and share similar cellular functions, which are context dependent. In particular, p110α pathway deregulation has been demonstrated in ovarian, breast, colon, and brain cancers. Hence, inhibitors targeting PI3K activities are major interest area for cancer treatment and therapy [1, 2].

Consistent with its mechanism of action, Buparlisib decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentration-dependent and pathway-specific manner. Tested in a panel of 353 cell lines, Buparlisib exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. Buparlisib shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. Buparlisib behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide.

As found with other PI3K inhibitors, Buparlisib possesses strong antiangiogenic activity. Hence, highly angiogenic tumors could be very sensitive to the compound. Buparlisib could, therefore, be used efficiently as second line treatment upon failure of approved antiangiogenic drugs such as sutent, or sorafenib, in the case of metastatic renal cell carcinoma. Of interest is the fact that Buparlisib possesses excellent brain penetration, hence, there is the possibility to treat advanced nonresectable highly angiogenic GBM, mostly in combination with temozolomide-based therapies [1].

Target modulation and good pharmacokinetic and pharmacodynamic correlation was achieved with Buparlisib in tumor-bearing mice. Significant and dose-dependent antitumor activity was observed at dose levels sufficient to shut down the PI3K pathway, showing the strong relationship between compound concentration, pathway inhibition and efficacy. Suboptimal dose of Buparlisib was enough to strongly enhance the antitumor activity of standard of care (cytotoxic or targeted agents) in various cancer types such as prostate (with Taxotere), HER2-amplified breast cancer, or gastric cancer (with Herceptin/trastuzumab) and GBM (with temozolomide) [1].

Researchers tested the biologic effects of Buparlisib in a set of glioma cell lines. Buparlisib treatment for 72 hours resulted in a dose-dependent growth inhibition and effectively blocked the PI3K/Akt signaling cascade. Although they found no obvious relationship between the cell line's sensitivity to Buparlisib and the phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) statuses, reserachers did observe a differential sensitivity pattern with respect to p53 status, with glioma cells containing wild-type p53 more sensitive than cells with mutated or deleted p53. Buparlisib showed differential forms of cell death on the basis of p53 status of the cells with p53 wild-type cells undergoing apoptotic cell death and p53 mutant/deleted cells having a mitotic catastrophe cell death [3].

In a review researchers have reported intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug with special emphasis on breast cancer [4].

1. Burger, M. T.; et. al. Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer. ACS Med Chem Lett 2011, 2(10), 774–779.
2. Maira, S. M.; et. al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 2012, 11(2), 317-328.
3. Koul, D.; et. al. Antitumor activity of NVP-BKM120--a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res 2012, 18(1), 184-195. (Kinase Glo assay data)
4. Geuna, E.; et. al. Buparlisib , an oral pan-PI3K inhibitor for the treatment of breast cancer. Expert Opin Investig Drugs 2015, 24(3), 421-431.