5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

Abstract

Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.

PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition

“…To identify novel predictive therapeutic vulnerabilities linked to PI3K/mTOR pathway inhibition, we treated 59 HNSCC cell lines with seven different PI3K/mTOR pathway inhibitors that were in clinical development at the start of this study (19)(20)(21)(22)(23)(24)(25)(26). Of the drug-cell line combinations, 95% met our predefined quality control cutoff.…”

Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

“…Improved yields were obtained using di(1‐adamantyl)‐ n‐butyl phosphine ( n BuPAd 2 ), a ligand known to be more effective for chlorinated substrates in Heck reactions involving imidazo[1,2‐ a ]pyridines, and this phosphine was retained for all subsequent work. The use of the 2‐iodotriazine 19 was also found to give superior results compared to chloride 18 , in terms of higher product yield and milder reaction conditions.…”

“…In order to prepare the direct imidazo[1,2-a]pyridine analogue of ZSTK474 (1)i tw as first necessary to prepare2 -(difluoromethyl)imidazo[1,2-a]pyridine (22), which was readily formed by treatment of the known aldehyde 21 [23] with DAST (Scheme 3). Heck reaction of 22 with chloride 18 gave the desired ZSTK474 analogue 23 in good yield.…”

“…Method B: A mixture of 17 (49 mg, 0.026 mmol), 4,4′‐(6‐iodo‐1,3,5‐triazine‐2,4‐diyl)dimorpholine ( 19 ) (94 mg, 0.025 mmol), Pd(OAc) 2 (1.2 mg, 0.0053 mmol), n BuPAd 2 (3.5 mg, 0.0098 mmol), K 3 PO 4 (110 mg, 0.052 mmol) in dry DMF (2 mL) was flushed with nitrogen and heated in an oil bath at 90 °C for 2 h. After dilution with water and extraction with CH 2 Cl 2 , the crude product was chromatographed on silica, eluting first with CH 2 Cl 2 /EtOAc (49:1), and then CH 2 Cl 2 /EtOAc (4:1), to give 20 (100 mg, 92 % yield); identical to above.…”

“…Purification by flash column chromatography on silica using CH 2 Cl 2 -EtOAc (1:3) gave 4-(4-chloro-6-(2-methylimidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-yl)morpholine (15) ( 20) Method A: Am ixture of 2-(trifluoromethyl)imidazo[1,2-a]pyridine (17) [19] (82 mg, 0.044 mmol), 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (18) [20] (125.7 mg, 0.044 mmol), Pd(PPh 3 ) 4 (254 mg, 0.022 mmol), Pd(OAc) 2 (49 mg, 0.022 mmol), K 2 CO 3 (122 mg, 0.088 mmol) in dioxane (5 mL) and water (1 mL) was degassed, flushed with nitrogen, and heated under reflux overnight. After dilution with water and extraction with CH 2 Cl 2 ,t he crude product was chromatographed on silica eluting with hexanes/EtOAc (1:1) [22] (94 mg, 0.025 mmol), Pd(OAc) 2 (1.2 mg, 0.0053 mmol), nBuPAd 2 (3.5 mg, 0.0098 mmol), K 3 PO 4 (110 mg, 0.052 mmol) in dry DMF (2 mL) was flushed with nitrogen and heated in an oil bath at 90 8Cf or 2h.A fter dilution with water and extraction with CH 2 Cl 2 ,t he crude product was chromatograph-ed on silica, eluting first with CH 2 Cl 2 /EtOAc (49:1), and then CH 2 Cl 2 / EtOAc (4:1), to give 20 (100 mg, 92 %yield);i dentical to above. (23) As olution of imidazo[1,2-a]pyridine-2-carbaldehyde (21) [23] (2.15 g, 14.72 mmol) in CH 2 Cl 2 was treated with (diethylamino)sulfur trifluoride (DAST) (4 mL, excess) and the mixture was stirred for 1h, when further DAST (3 mL) was added and stirring was continued for aa nother 2h.T he reaction mixture was poured into ice water, basified with aq NH 3, extracted into CH 2 Cl 2 (4 30 mL) and dried (Na 2 SO 4 ).…”