TGR-1202: A Novel, Targeted PI3Kδ Inhibitor in Multiple Myeloma

The bone marrow microenvironment contributes to the pathogenesis of Multiple Myeloma (MM) by promoting the oncogenic process including drug resistance. High expression levels of the PI3Kδ isoform in patient MM cells implicate this target as a novel and attractive intervention strategy aimed at attenuating the progression of the disease. Herein, we describe the biological and pharmacokinetic properties of TGR-1202, a novel and small molecule PI3Kδ inhibitor with scope to be developed as a clinical candidate for patients with relapsed and/or refractory MM.

Activity of TGR-1202 on individual PI3K isoforms was determined in enzyme, cell, and whole blood based assays. Potency of the compound was confirmed viaMM cell viability and apoptosis assays besides testing for inhibition of pAkt, a downstream kinase regulating cell survival and growth. Additionally, the compound was tested for potency in viability, apoptosis, and Akt phosphorylation assays using immortalized and MM patient derived primary cells. ADME and pharmacokinetic properties of the molecule were also determined.

TGR-1202 demonstrated significant potency against PI3Kδ (22. 2 nM) with several fold selectivity over the α (>10000), β (>50), and γ (>48) isoforms. Additionally, the compound inhibited B-cell proliferation (24. 3 nM) and FcεR1 induced CD63 expression in human whole blood basophils (68. 2 nM) indicating specificity towards the delta isoform. The addition of 5 μM TGR-1202 to dexamethasone (0. 55 μM) caused a dramatic shift in GI₅₀ of MM-1S cells compared to that of either TGR-1202 (9. 7 μM) or dexamethasone (18. 3 μM) alone. Further viability testing demonstrated that the compound caused a dose-dependent inhibition (>50% @ 1–3 μM) in growth of immortalized (U266B1 and MM-1R) as well as patient-derived MM cells. Reduction in viability was accompanied by a reduction in pAKT (>80% @ 3 μM) along with induction of apoptosis in both cell lines and patient samples. Pharmacokinetic studies across species indicated good oral absorption (>40% bioavailability for mice, rat, and dog) with favorable plasma concentrations (3–10 μM @ 20 mg/kg for mice, rat, and dog) relevant for efficacy.

Data demonstrate the therapeutic potential of TGR-1202 in MM viainhibition of the PI3Kδ pathway. Data from immortalized as well as primary patient-derived cells justify further evaluation of this molecule in MM. Combination therapy of TGR-1202 and dexamethasone in a mouse MM-1S xenograft model is currently ongoing.

Vakkalanka:Rhizen Pharmaceuticals S A: Employment, Equity Ownership. Viswanadha:Incozen Therapeutics: Employment. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership.