Additionally, PKHD-5 has demonstrated significant antitumor proliferation effects without significant toxicity. In summary, the results suggest that PKHD-5 is a promising candidate for further preclinical studies of hepatocellular carcinoma therapy.

Provided herein are novel indazole compounds as PKMYT1 kinase inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Compound 7 demonstrated strong PKMYT1-specific inhibition, a subsequent decrease in CDK1 phosphorylation, and antitumor efficacy in vitro, as well as enhanced metabolic stability, favorable pharmacokinetic and bioavailability properties, and potent antitumor in vivo efficacy. Our findings indicate that compound 7 is a promising PKMYT1 inhibitor for the treatment of advanced cancers with cell cycle defects.

P1, N=90, Recruiting, Acrivon Therapeutics

Overall, our findings provided insights into the development of novel therapeutic strategies for CDDP-R BC.

This perspective summarizes, for the first time, the PKMYT1 structure, function, and inhibitors in both the literature and patent applications reported to date. Compounds are described focusing on their design and optimization process, structural features, and biological activity with the aim to promoting further drug discovery efforts targeting PKMYT1 as a potential precision therapy.

P1, N=124, Recruiting, Exelixis

Herein, we conducted virtual screening of a natural product library, and in vitro enzyme experiments demonstrated that EGCG, GCG, and luteolin exhibited potent inhibitory activities with IC50 values of 0.137 μM, 0.159 μM, and 1.5 μM, respectively. Subsequently, analysis of the hit compounds and RP-6306, using different molecular simulation methods, revealed that stable hydrogen bonds with Asp251 and Glu157 in the DFG region were vital for binding to PKMYT1, more so than hydrogen bonds in the hinge and loop regions.

Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E-high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype.

It also suppressed proliferation of the CCNE1-amplified HCC1569 breast cancer cell line and showed synergistic cytotoxicity in combination with gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction of key binding interactions between the inhibitors and residues Asp251 and Tyr121 of PKMYT1 greatly enhanced the potency and selectivity of the compounds.

P1, N=52, Recruiting, Schrödinger, Inc. | Not yet recruiting --> Recruiting

Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer.

"Foundation Medicine...announced that it has formed a collaboration with Repare Therapeutics, a leading clinical-stage precision oncology company, to provide prospective genomic profiling to patients in Repare’s ongoing Phase I/Ib MYTHIC study (NCT04855656) of lunresertib alone or in combinations in genomically-defined patient populations. The companies are also exploring opportunities to develop FoundationOne CDx, a tissue-based comprehensive genomic profiling test, as a companion diagnostic for the lunresertib program....Foundation Medicine is the global leader in companion diagnostic approvals with approximately 60% of all U.S. companion diagnostic approvals for next generation sequencing testing."

In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

In a CCNE1-amplified triple-negative cell model (HCC1569), treatment with the PKMYT1 inhibitor RP-6306 significantly reduced tumor growth. CCNE1 amplification in BCs is associated with greater genomic instability and characterizes a group of metastatic BCs with poor response to standard of care therapies. Novel therapies targeting CCNE1-amplified tumors are under evaluation in preclinical and clinical studies.

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.