PKMYT1 (Protein Kinase Membrane Associated Tyrosine/Threonine 1)

Importantly, genetic or pharmacological disruption of this GPRIN1-CDK1-PI3K/Akt axis completely abrogated tumorigenesis in vitro and in vivo. Taken together, these results reveal GPRIN1 as a master regulator whose dual transcriptional and post-translational control of CDK1 integrates cell cycle progression with mitochondrial homeostasis, suggesting that targeting GPRIN1 may represent a highly specific therapeutic strategy in this lethal malignancy.

Herein, we report the rational design and characterization of a novel PKMYT1 inhibitor A4 that uniquely leverages an underutilized sulfur-lone pair interaction to achieve exceptional potency and favorable ADME properties. Our study not only expands the structural diversity of PKMYT1 inhibitors but also demonstrates the broader potential of nonbonding interaction engineering in small-molecule drug design.

This study establishes PKMYT1 as a critical oncogene, an independent prognostic biomarker, and a modulator of the tumor immune microenvironment in LUAD. These findings highlight PKMYT1's potential as a promising therapeutic target and a candidate biomarker for patient stratification, offering new insights for targeted therapy strategies in LUAD.

Inhibition of the FoxM1/Snail/EMT pathway reversed PKMYT1-induced metastasis in mice. Collectively, our findings identify the PKMYT1/FoxM1/Snail axis as a driver of ccRCC metastasis via EMT induction, highlighting PKMYT1 as a potential therapeutic target for ccRCC.

The hinge-binding carboxamide cyclized derivative B3 demonstrated potent enzymatic inhibition (IC50 = 3.5 nM) and cellular CDK1 phosphorylation suppression (IC50 = 65-114 nM), selectively inhibited proliferation of CCNE1-amplified cancer cells (IC50 = 0.56-0.88 μM) through induction of γH2AX accumulation. Furthermore, compared to the first-in-class PKMYT1 inhibitor RP-6306, B3 exhibited enhanced solubility (176 vs 45 μM) and favorable in vivo metabolic stability (mouse clearance 58.2 vs 85.7 mL/min/kg), underscoring cyclization as a productive design strategy to improve drug-likeness of PKMYT1 inhibitors.

PKMYT1 is a pivotal dual regulator of tumor progression and immune evasion in CRPC. Our findings provide a compelling preclinical rationale for targeting PKMYT1 as a novel strategy to reprogram the tumor immune microenvironment and overcome resistance to immunotherapy.

Thus, FOXM1 reshapes the TACC3-KAT2A interaction, while DNMT1 drives context-dependent DNA methylation, activating the CDK1-inhibitory kinase PKMYT1. We uncovered TACC3-KAT2A as an emerging regulatory axis caused by alternative splicing in HCC and propose FOXM1-driven TACC3 inhibition to synergistically disrupt mitotic fidelity and transcriptional regulation, potentially offering new therapeutic avenues for HCC with reduced toxicity to the normal liver.

Furthermore, two prodrug derivatives of compound 20 were designed to improve aqueous solubility, achieving dose-proportional systemic exposure in rats during dose-escalation preclinical toxicity studies. Additionally, the combination of prodrug 22 with TrodelvyⓇ, a TROP2 ADC, demonstrated synergistic antitumor activity in triple-negative breast cancer MDA-MB-231 xenograft models.

We evaluated lunresertib (RP-6306), a selective first-in-class PKMYT1 inhibitor, in CCNE1 -amplified and wild-type GEA cell lines to define its effects on cell viability, DNA damage, and gene expression changes...In a syngeneic murine model of CCNE1 -amplified gastric cancer, we further identified that PKMYT1 inhibition induced T cell infiltration and tumor microenvironment remodeling, and synergized with anti-PD-1 therapy to drive tumor regression. Together, these results support further development of PKMYT1 inhibition in combination with PD-1 blockade for CCNE1 -amplified GEA.

Overexpression of PKMYT1 restored the malignant phenotypes of USP49-deficient TNBC cells. Collectively, these findings uncover a novel USP49-PKMYT1 regulatory axis that drives TNBC progression.

Here, we demonstrate that coinhibition of ATR (RP-3500) and PKMYT1 (RP-6306) induces synthetic lethality in Rb1-deficient breast cancers by disrupting both S-G2 and G2-M checkpoints...Clinically, a retrospective analysis of stage IV breast cancer datasets revealed that Rb1-low tumors display reduced DNA repair pathway activity in triple-negative and CDK4/6 inhibitor-resistant luminal breast cancers. These results identify Rb1 loss as a predictive biomarker for ATR/PKMYT1-targeted therapy, offering a potential precision treatment strategy for advanced breast cancers.

Additionally, XH-30 achieves a synergistic antitumor effect with the PARP1 inhibitor Olaparib by downregulating the expression of BRCA1/2. In conclusion, we have identified a potent PKMYT1 inhibitor, XH-30, which provides a novel therapeutic option for treating P53-mutated TNBC.