The multifactorial nature of cancer requires treatment that involves simultaneous targeting of associated overexpressed proteins and cell signaling pathways, possibly leading to synergistic effects. Herein, we present a systematic study that involves the simultaneous inhibition of human topoisomerases (hTopos) and histone deacetylases (HDACs) by multitargeted quinoline-bridged hydroxamic acid derivatives. These compounds were rationally designed considering pharmacophoric features and catalytic sites of the cross-talk proteins, synthesized, and assessed for their anticancer potential. Our findings revealed that the compound 5c significantly produced anticancer effects in vitro and in vivo by reducing the tumor growth and its size in the A549 cell-induced lung cancer xenograft model through multiple mechanisms, primarily by multi-inhibition of hTopoI/II and HDACs, especially HDAC1 via atypical binding. The present paper discusses detailed mechanistic biological investigations, structure-activity effects supported by computational docking studies, and DMPK studies and provides future scope for lead optimization and modification.

EGFR activation in colorectal and breast cancer stimulates downstream pathways like Ras/Raf/MEK/ERK and PI3 K/Akt, fostering cell proliferation, invasion, metastasis, and therapy resistance, underscoring its significance as a therapeutic target in both cancers. In the present work, we rationally designed (E)-4-methyl-1-((3-oxo-1-phenylbutyl)amino)-4-styryl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (RA-22) as EGFR inhibitor. Our research investigates the role of RA-22 as a target molecule for EGFR, exploring its anticancer potential and mechanism of action across breast cancer and colorectal cancer cell lines. The in-vitro studies showed its cytotoxic response towards MDA-MB-231 and HCT-116 and its inhibitory effect on cancer stem cells in mammosphere/spheroid culture. The compound downregulates the oncogenic signalling proteins like STAT-3, AKT, PAN-AKT, and ERK and also reduces the expression of the anti-apoptotic protein Bcl-2 and increases the apoptotic proteins like Cleaved-PARP, Cleaved-Caspase-3, and Cleaved-Caspase-9.

Two lead compounds, 5a and 5l, designed on an imidazo[1,2- a ]quinoxaline template, emerged as potent EGFR inhibitors and anti-lung cancer agents.

Epidermal growth factor receptor (EGFR) is an oncogenic drug target and plays a critical role in several cellular functions including cancer cell growth, survival, proliferation, differentiation, and motility. Several small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) have been approved for targeting intracellular and extracellular domains of EGFR, respectively. However, cancer heterogeneity, mutations in the catalytic domain of EGFR, and persistent drug resistance limited their use. Different novel modalities are gaining a position in the limelight of anti-EGFR therapeutics to overcome such limitations. The current perspective reflects upon newer modalities, importantly the molecular degraders such as PROTACs, LYTACs, AUTECs, and ATTECs, etc., beginning with a snapshot of traditional and existing anti-EGFR therapies including small molecule inhibitors, mAbs, and antibody drug conjugates (ADCs). Further, a special emphasis has been made on the design, synthesis, successful applications, state-of-the-art, and emerging future opportunities of each discussed modality.

Pyrimidines-based drugs are one of the most important drugs for novel and recurring viruses, including the coronavirus. This chapter deals with 41 FDA-approved five-membered ring fused pyrimidine-based drugs, their synthetic strategies, and pharmacological activities.

Background: The EGFR is overexpressed in numerous cancers.So, it becomes one of the most favorable drug targets.Single-acting EGFR inhibitors on prolong use induce resistance and side effects.Inhibition of EGFR and/or its interacting proteins by dual/combined/multitargeted therapies can deliver more efficacious drugs with less or no resistance. Objective: The review delves deeper to cover the aspects of EGFR.mediated endocytosis, leading to its trafficking internaliration, and crosstalk(s) with I IDACs. Methods and Results: This review is put forth to congregate relevant literature evidenced on EGFR, its impact on cancer prognosis, inhibitors, and its trafficking regulation by acetylation along with the current strategies involved in targeting these proteins (EGER.and EIDACs) successfully by involving dual/hybrid/combination chemotherapy. Conclusion: The current information on cross-talk of EGFR and EIDACs would likely assist researchers in designing and developing dual or multitargeted inhibitors through combining the required pharnracophores.

Background: The EGFR is overexpressed in numerous cancers. So, it becomes one of the most favorable drug targets. Single-acting EGFR inhibitors on prolong use induce resistance and side effects. Inhibition of EGFR and/or its interacting proteins by dual/combined/multitargeted therapies can deliver more efficacious drugs with less or no resistance. Objective: The review delves deeper to cover the aspects of EGFR mediated endocytosis, leading to its trafficking, internalization, and crosstalk(s) with HDACs. Methods and Results: This review is put forth to congregate relevant literature evidenced on EGFR, its impact on cancer prognosis, inhibitors, and its trafficking regulation by acetylation along with the current strategies involved in targeting these proteins (EGFR and HDACs) successfully by involving dual/hybrid/combination chemotherapy. Conclusion: The current information on cross-talk of EGFR and HDACs would likely assist researchers in designing and developing dual or multitargeted inhibitors through combining the required pharmacophores.