Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model

Abstract

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.

Further modifications of 1H‐pyrrolo[2,3‐b]pyridine derivatives as inhibitors of human neutrophil elastase

“…In the first step, the nitrogen at position 1 of intermediate 3a (Joydev et al, ) was protected with benzensulfonyl chloride to obtain compound 8 (Liu et al, ), which subsequently was treated with tetrakis(triphenylphosphine)palladium(0), 2 M sodium carbonate solution, and the appropriate boronic acid in hot anhydrous toluene to obtain the corresponding 5‐pyrrolo[2,3‐b]pyridine derivatives 9a‐g . The protecting group at position N‐1 was then removed with tetrabutylammonium fluoride (TBAF) in hot anhydrous tetrahydrofuran, resulting in pyrrolo[2,3‐b]pyridines 10a‐g ( 10a , Laha et al, ; 10c and 10d , Ibrahim et al, ; 10f and 10g , Singh et al, ). Reaction of these compounds with hexamethylenetetramine (HMTA) in acetic acid at reflux resulted in the 3‐formyl derivatives 11a‐g ( 11g , Ibrahim et al, ), which, when treated with hydroxylamine hydrochloride ( 12a‐g ), dehydrated with POCl 3 ( 13a‐g ), and benzoylated at position 1 with m‐toluoyl chloride, led to final compounds 14a‐g .…”

“…General procedure for compounds 11a‐f. A mixture of the appropriate 1H‐pyrrolo[2,3‐b]pyridine derivative 10a‐f (0.95 mmol) ( 10a , Laha et al, ; 10c and 10d , Ibrahim et al, ; 10f , Singh et al, ) and HMTA (1.43 mmol) in glacial acetic acid (3 mL) was heated under reflux for 6 hr. The reaction mixture was cooled at room temperature and diluted with cold water.…”

AKT isoforms have discrete expression in triple negative breast cancers and roles in cisplatin sensitivity

“…To explore the dominant AKT isoform for treatment of drug resistant triple negative breast cancer; we transduced the mouse triple negative breast cancer cell line, 4T1, with shRNA targeting AKT1/2/3 and subcutaneously implanted 1 × 10 6 cells into female Balb/c mice for investigating in vivo efficacy. 4T1 cell line establishes highly proliferative and metastatic tumors in immunocompetent BALB/c mice and also models human triple-negative breast cancer [27]. Co-treatment with cisplatin in mice carrying xenografts formed from knockdown of AKT2 (4T1 shAKT2) and AKT3 (4T1 shAKT3) in 4T1 cells dramatically attenuated tumor formation in mice after two weeks as compared with that of mice with knockdown of AKT1 (4T1 shAKT1) treated with cisplatin ( Figure 8A).…”

Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

“…95 The meriolin analog 16 is a potent inhibitor of CDK2 and 9 (IC 50 values = 5.5 and 24 nM), showing a remarkable intravenous PK profile and has shown 90% TGI in the TNBC model at 15 mg/kg IP (Q3D × 21). 96 Nankai University identified a benzimidazole-linked aminopyrimidine 17 as a dual CDK4/VEGFR2 inhibitor having structural similarity to that of abemaciclib. It shows excellent in vitro and in vivo efficacy in the cervical cancer SiHa model at 40 mg/kg, PO (QD × 21).…”