P1, N=364, Recruiting, Repare Therapeutics | N=180 --> 364

P1, N=24, Active, not recruiting, University Health Network, Toronto | Not yet recruiting --> Active, not recruiting | Initiation date: Dec 2023 --> Mar 2024

P1, N=36, Active, not recruiting, Repare Therapeutics | Recruiting --> Active, not recruiting | N=104 --> 36

There are not many inhibitors of this emerging, potentially clinically important kinase. Herein, the valuable insight into structural features and binding mechanisms of diaminopyrimidines, aminoquinolines, quinazolines, pyrido[2,3-d]pyrimidines, pyrazolo[3,4-d]pyrimidines, and pyrrolo[2,3-b]quinoxalines, as well as finally made a general scheme of fragmented structures of Myt1 inhibitors with the enzyme, offer potential frameworks useful for future directions, for further chemical optimizations, in the discovery and the design of novel effective structures, potential therapeutics.

P1, N=180, Recruiting, Repare Therapeutics | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Oct 2023 --> Jun 2026

P1, N=104, Active, not recruiting, Repare Therapeutics | Recruiting --> Active, not recruiting | Trial primary completion date: Oct 2023 --> Dec 2024

Importantly, our lead compound, featuring a tetrahydropyrazolopyrazine ring, exhibits remarkable selectivity over WEE1, a related kinase associated with bone marrow suppression upon inhibition. Optimization of potency and physical properties resulted in the discovery of compound 21, a novel MYT1 inhibitor, exhibiting optimal pharmacokinetic properties and promising in vivo antitumor efficacy.

P2, N=78, Recruiting, Canadian Cancer Trials Group

We demonstrate the synergistic effects of WEE1 inhibitor (MK1775/AZD1775) and PKMYT1 inhibitor (RP6306) in a panel of TNBC and ER+ve breast cancer cells with acquired palbociclib resistance (PalboR). Overall, this study highlights the potential therapeutic benefits of dual inhibition of WEE1 and PKMYT1 in overcoming CDK4/6 inhibitor resistance in TNBC and ER+ve breast cancer patients. These findings provide a rationale for future clinical trials aimed at exploring the clinical utility of this combination therapy.

P1, N=24, Not yet recruiting, University Health Network, Toronto

No abstract available

No abstract available

No abstract available

P2, N=78, Recruiting, Canadian Cancer Trials Group | Not yet recruiting --> Recruiting | Initiation date: Jan 2023 --> Apr 2023

P1, N=180, Recruiting, Repare Therapeutics | N=120 --> 180 | Trial completion date: Apr 2024 --> Dec 2024

Substantial intratumoral spatial heterogeneity of CCNE1 copy number when measured by FISH was observed across ovarian and uterine tumors. The potential impact of CCNE1 amplification heterogeneity, cyclin E1 protein levels and CCNE1 amplification fragment size on response to RP-6306 in preclinical models are currently being investigated and will be reported.

Besides, the down-regulation of PKMYT1 induced apoptosis in vitro. As a result, PKMYT1 might be a biomarker for prognosis and a therapeutic target for TNBC.

Taken together, the results of the present study have shown that a high expression level of PKMYT1 is associated with poor prognosis of osteosarcoma, and that PKMYT1 is able to aggravate the malignant progression of MG63 cells via negatively regulating the NF κB pathway, suggesting that PKMYT1 may be a potential molecular therapeutic target for the treatment of osteosarcoma.

Our study suggests that PKMYT1 functions as an oncogene and may be a new target for HCC treatment.

This work reveals the anti-tumor effect of PKMYT1 in LUAD and provides evidence to clarify the dual roles of PKMYT1 in tumor progression. Moreover, our findings broaden the current understandings on AKT1 activation and identify PKMYT1 as a potential negative regulator of AKT1 kinase activity, providing further insights into targeting the AKT pathway in LUAD.

P2, N=78, Not yet recruiting, Canadian Cancer Trials Group

RP-6306 is a first-in-class highly potent and selective PKMYT1 inhibitor currently in clinical trials as a single agent (NCT04855656) and in combination with gemcitabine and irinotecan-based therapy (NCT05147350 and NCT05147272). Together, these results provide a strong rationale for clinical development of this combination in CCNE1-amplified cancer that has therapeutic potential across several solid tumor types where platins are used.

RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.

P1, N=120, Recruiting, Repare Therapeutics | N=60 --> 120 | Trial completion date: Jun 2023 --> Apr 2024 | Trial primary completion date: Apr 2023 --> Oct 2023

To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumour regressions when combined with gemcitabine in models of CCNE1 amplification. CCNE1 overexpression disrupts CDK1 homeostasis at least in part through an early activation of the MMB-FOXM1 mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

Moreover, miR-601 was attenuated by c-Myb at transcriptional level. Taken together, our studies reveal that miR-601 is a suppressive gene negatively correlated with malignancy of OS.

Our studies show that inhibition of PKMYT1 kinase activity impairs the growth of CCNE1 amplified cancer cell lines both in vitro and in vivo and stands to benefit cancer patients with CCNE1 amplification. A Phase I clinical trial (NCT04855656- Mythic Study) is currently underway to evaluate RP-6306 in patients with advanced solid tumors.

In addition, PKMYT1 was demonstrated to bind to CCNA2, and knocking down PKMYT1 resulted in inhibitory effects on cell proliferation, colony formation ability, migration, invasion and EMT by downregulating CCNA2 expression. PKMYT1 was observed to regulate the proliferation, migration and EMT of OSCC cells by targeting CCNA2, which may be used in the future to improve OSCC treatment.

The PKMYT1 gene holds the potential as a new potential biomarker. Therefore, further studies are clearly needed to elaborate our findings.

Mechanistic study shows that PKMYT1AR/ miR-485-5p /PKMYT1 axis promotes cancer stem cells (CSCs) maintenance in NSCLC via inhibiting β-TrCP1 mediated ubiquitin degradation of β-catenin proteins, which in turn causes enhanced tumorigenesis. Our findings reveal the critical role of PKMYT1AR/miR-485-5p /PKMYT1 axis during NSCLC progression, which could be used as novel therapeutic targets in the future.

P1, N=60, Repare Therapeutics