Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K/mTOR dual inhibitor for the treatment of acute myeloid leukemia.

PI3K-Akt-mTOR pathway is a highly activated signal transduction pathway in human hematological malignancies and has been validated as a promising target for acute myeloid leukemia (AML) therapy. Herein, we designed and synthesized a series of 7-azaindazole derivatives as potent PI3K/mTOR dual inhibitors based on our previously reported FD223. Among them, compound FD274 showed excellent dual PI3K/mTOR inhibitory activity, with IC50 values against PI3Kα/ß/γ/δ and mTOR of 0.65 nM, 1.57 nM, 0.65 nM, 0.42 nM, and 2.03 nM, respectively, superior to compound FD223. Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC50 values of 0.092 µM and 0.084 µM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.

Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer.

Phosphoinositide-3-kinase (PI3K) involves in regulation of proliferation, cell cycle, and apoptosis, and is overexpressed in most of human malignant tumors. Therefore, the development of PI3K inhibitors has attracted great interest in tumor treatment. In this study, we designed and synthesized a series of 2-aminopyridine derivatives via a bioisosterism strategy. Among them, compound MR3278 showed superior PI3Kδ inhibitory activity (IC50 = 30 nM), as well as higher inhibitory activity to most of AML cells (e.g., MOLM-16 and Mv-4-11 cells with IC50 values of 2.6 µM and 3.7 µM, respectively) than Idelalisib. Further cell studies indicated that MR3278 could induce G2/M phase arrests and cell apoptosis of Mv-4-11 cells via PI3K dependent pathway in a dose dependent manner. In addition, in silico physicochemical and ADMET evaluation revealed its drug-like properties with satisfactory toxicity profiles. These results indicate that MR3278 can be identified as a promising new lead compound to the current PI3Kδ inhibitor and is worthy of further profiling.

A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia.

Aberration of PI3K signaling pathway has been confirmed to be associated with several hematological malignancies including acute myeloid leukemia (AML). FD268, a pyridinesulfonamide derivative characterized by the conjugation of 7-azaindole group, is a newly identified PI3K inhibitor showing high potent enzyme activity at nanomole concentration. In this study, we demonstrated that FD268 dose-dependently inhibits survival of AML cells with the efficacy superior to that of PI-103 (pan-PI3K inhibitor) and CAL-101 (selective PI3Kδ inhibitor) in the tested HL-60, MOLM-16, Mv-4-11, EOL-1 and KG-1 cell lines. Further mechanistic studies focused on HL-60 revealed that FD268 significantly inhibits the PI3K/Akt/mTOR signaling pathway, promotes the activation of pro-apoptotic protein Bad and downregulates the expression of anti-apoptotic protein Mcl-1, thus suppressing the cell proliferation and inducing caspase-3-dependent apoptosis. The bioinformatics analysis of the transcriptome sequencing data also indicated a potential involvement of the PI3K/Akt/mTOR pathway. These studies indicated that FD268 possesses high potent activity toward AML cells via inhibition of PI3K/Akt/mTOR signaling pathway, which sheds some light on the pyridinesulfonamide scaffold for further optimization and investigation.

Development of anti-breast cancer PI3K inhibitors based on 7-azaindole derivatives through scaffold hopping: Design, synthesis and in vitro biological evaluation.

Breast cancer is the cancer with the highest incidence all over the world. Phosphatidylinositol 3-kinase is an important regulator of intracellular signaling pathways, which is frequently mutated and overexpressed in majority of human breast cancers, and the inhibition of PI3K has been considered as a promising approach for the treatment of the cancer. Here, we report our design and synthesis of new 7-azaindole derivatives as PI3K inhibitors through the scaffold hopping strategy. By varying the groups at the 3-position of 7-azaindole, we identified a series of potent PI3K inhibitors, whose antiproliferative activities against two human breast cancer MCF-7 and MDA-MB-231 cell lines were evaluated. Representative derivatives FD2054 and FD2078 showed better activity than BKM120 in antiproliferation, reduced the levels of phospho-AKT and induced cell apoptosis. All these results suggested that FD2054 and FD2078 are potent PI3K inhibitors that could be considered as potential candidates for the development of anticancer agents.

Discovery of cinnoline derivatives as potent PI3K inhibitors with antiproliferative activity.

Cinnoline is a potential pharmacophore which has rarely been reported for uses as PI3K inhibitors. In this study, a series of cinnoline derivatives were developed as PI3K inhibitors and evaluated for enzymatic and cellular activities. Most compounds displayed nanomolar inhibitory activities against PI3Ks, among which 25 displayed high LLE and micromolar inhibitory potency against three human tumor cell lines (IC50 = 0.264 µM, 2.04 µM, 1.14 µM).

Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3Kδ inhibitor: Design, synthesis and biological evaluation.

Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro studies revealed that FD223 displays high potency (IC50 = 1 nM) and selectivity (29-51 fold over other PI3K isoforms) against PI3Kδ, and exhibits efficient inhibition of the proliferation of AML cell lines (MOLM-16, HL-60, EOL-1 and KG-1) by suppressing p-AKT Ser473 thus causing G1 phase arrest during the cell cycle. Further given the favorable pharmacokinetic (PK) profiles of FD223, in vivo studies were evaluated using xenograft model in nude mice, confirming its significant antitumor efficacy meanwhile with no observable toxicity. All these results are comparable to the positive group of Idelalisib (CAL-101), indicating that FD223 has potential for further development as a promising PI3Kδ inhibitor for the treatment of leukemia such as AML.

In situ embedding dual-Fe nanoparticles in synchronously generated carbon for the synergistic integration of magnetic resonance imaging and drug delivery.

In situ incorporating versatile magnetic iron nanoparticles into ordered mesoporous carbon (OMC) by means of synthetic methodology for functional integration is a great challenge. Inspired by the phenomenon of uniovular twins in nature, a homometallic [Fe9(µ3-O)4(O3PPh)3(O2CCMe3)13] ({Fe9P3}) cluster was synthesized and used as the ovulum to in situ produce dual-Fe nanoparticle (γ-Fe2O3 and Fe(PO3)3)-functionalized OMC (dual-Fe/OMC). In vitro magnetic resonance imaging (MRI) studies showed a longitudinal relaxation (r 1) and transverse relaxation (r 2) of 9.74 and 26.59 mM-1 s-1 with a r 2/r 1 ratio of 2.73 at 0.5 T. The MRI performances were further examined by mouse model with a subcutaneous HeLa tumor. In addition, the low cytotoxicity, considerable loading capacity and delivery of doxorubicin hydrochloride (DOX) were also studied in vitro. These results demonstrate the feasibility of the concept of uniovular twins in the one-pot preparation of dual-Fe/OMC for functional integration.

Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity.

The phosphoinositide 3-kinase (PI3K) inhibitors potently inhibit the signaling pathway of PI3K/AKT/mTOR, which provides a promising new approach for the molecularly targeted cancer therapy. In this work, a novel series of 7-azaindole scaffold derivatives was discovered by the fragment-based growing strategy. The structure-activity relationship profiles identified that the 7-azaindole scaffold derivatives exhibit potent activity against PI3K at molecular and cellular levels as well as cell proliferation in a panel of human tumor cells.

Preparation of highly dispersed γ-Fe2O3 and GdPO4 co-functionalized mesoporous carbon spheres for dual-mode MR imaging and anti-cancer drug carrying.

There is great interest in integration of paramagnetic gadolinium compounds and superparamagnetic iron oxide-based nanoparticles into ordered mesoporous carbon spheres (OMCSs) as a combined platform for T1- and T2-weighted magnetic resonance (MR) imaging and drug carrying. In this work, highly dispersed γ-Fe2O3 and GdPO4 nanoparticle co-functionalized mesoporous carbon spheres were successfully prepared using a 3d-4f heterometallic cluster of [Fe6Gd6(µ3-O)2(CO3)(O3PPh)6(O2CtBu)18] as the precursor. The study reveals that multi-scale confinement effects play a role in concurrent generation of Fe and Gd nanoparticles in the carbon matrix. In addition, dual-mode MR imaging and drug carrying properties were evaluated by in vitro experiments, showing satisfactory r1 and r2 relaxivity values of 8.2 and 94.3 mM-1 s-1, respectively, and doxorubicin hydrochloride (DOX) carrying amount of 132 mg g-1, suggesting potential as a combined system for diagnosis and therapy.