Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer

Abstract

Breast cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic structural optimization was conducted to afford 42, which exhibited strong inhibition on CDK4/6 and showed high selectivity among 205 kinases. 42 possessed excellent safety profiles (LD 50 > 5,000 mg/kg), favorable pharmacokinetic properties (F % = 43%), and potent efficacy in reducing the burden of breast cancer in vivo. In conclusion, we offered a highly selective CDK4/6 inhibitor, which could be used as a great candidate for further preclinical studies of breast cancer.

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation

“…However, in the last 200 ns of the simulation, hydrogen bonds were mainly formed with H100 for 80.27% occupancy ( Supplementary Figure S13 ). The formation of these two hydrogen bonds, which formed between abemaciclib and the hinge loop of CDK6, was consistent with the results of experimental and theoretical studies ( Yuan et al, 2021 ; Chen et al, 2022 ; Sokolsky et al, 2022 ; Wang et al, 2023 ). In addition, the hydrogen bond between the atom N4 of abemaciclib and the NZ atom of K43 was not unstable from the occupancy with 22.07% for the 500 ns simulation and 20.74% for the last 200 ns simulation, respectively.…”

“…The phosphorylated Rb induces the release of the critical transcription factor early 2 factor (E2F) to initiate the transcription of target genes, thereby facilitating the activation of various signaling pathways, including the G1/S transition, mitochondrial dynamics, and metabolism ( Sanchez-Martinez et al, 2015 ; Ingham and Schwartz, 2017 ; Matson and Cook, 2017 ; Sanchez-Martinez et al, 2019 ). When CDK4/6 is inhibited, the G1 phase of proliferating cells is blocked ( Yuan et al, 2021 ; Chen et al, 2022 ; Watt and Goel, 2022 ; Yousuf et al, 2022 ). Additionally, CDK4/6 is disordered in numerous cancers ( Wesierska-Gadek et al, 2009 ; Sanchez-Martinez et al, 2019 ; Yuan et al, 2021 ; Ghafouri-Fard et al, 2022 ; Kargbo, 2022 ; Yousuf et al, 2022 ; Zabihi et al, 2022 ), such as breast cancer ( Gelbert et al, 2014 ; Chen et al, 2022 ; Watt and Goel, 2022 ), osteosarcoma ( Wang and Bao, 2022 ), and acute megakaryoblastic leukemia ( Qi et al, 2022 ).…”

“…When CDK4/6 is inhibited, the G1 phase of proliferating cells is blocked ( Yuan et al, 2021 ; Chen et al, 2022 ; Watt and Goel, 2022 ; Yousuf et al, 2022 ). Additionally, CDK4/6 is disordered in numerous cancers ( Wesierska-Gadek et al, 2009 ; Sanchez-Martinez et al, 2019 ; Yuan et al, 2021 ; Ghafouri-Fard et al, 2022 ; Kargbo, 2022 ; Yousuf et al, 2022 ; Zabihi et al, 2022 ), such as breast cancer ( Gelbert et al, 2014 ; Chen et al, 2022 ; Watt and Goel, 2022 ), osteosarcoma ( Wang and Bao, 2022 ), and acute megakaryoblastic leukemia ( Qi et al, 2022 ). Thus, CDK4/6 is an effective anticancer drug target, especially in hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer.…”

Recent Advances in Synthetic Routes to Azacycles

“…N -heterocycles have been employed in many industries, including as dyes, agrochemicals, and materials [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. In pharmaceuticals, small-molecule drugs contain nitrogen-containing heterocycles and exhibit diverse bioactivities including anti-Alzheimer’s, antivirus, and anticancer behavior [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Thus, a series of studies on the synthesis and functionalization of many N -heterocyclic compounds, such as indoles, imidazoles, pyrrolidines, indolizines, and quinolines, as well as their application, has been carried out.…”

Design, synthesis, and anti‐breast cancer activity evaluation of endoperoxide‐type pyrido/pyrrolo[2,3‐d]pyrimidine derivatives

“…Most breast cancers display cyclin D overexpression and/or CDK 4/6 overactivation. CDK 4/6 inhibitors developed in recent decades were proven to be effective drugs for the treatment of breast cancer [8]. Three selective CDK 4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) [9] were approved by Food and Drug Administration for breast cancer therapeutic intervention between 2015 and 2017.…”