- |||||||||| ulevostinag (MK-1454) / Merck (MSD)
Discovery and development of MK-1454, a therapeutic cyclic dinucleotide STING agonist (Room 202 (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_8414;
The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. Finally, from these complex subunits, a novel thiophosphorylation reaction and a multi-step biocatalytic cascade enabled by the directed evolution of engineered enzymes were developed, providing a diastereoselective synthesis of this complex structure in unprecedented yield and efficiency.
- |||||||||| ulevostinag (MK-1454) / Merck (MSD)
Accelerating drug development through innovation for the stereoselective synthesis of cyclic dinucleotide MK-1454 (Sagamore Ballroom 6 (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_3987;
From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high-yielding cascade process. Overall, these developments and innovations led to vast reductions in waste production and substantial gains in sustainability, efficiency, and process safety.
- |||||||||| ulevostinag (MK-1454) / Merck (MSD)
Biocatalytic, stereoselective synthesis of a cyclic dinucleotide MK-1454 (Room 203 (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_324;
This biocatalytic cascade obviated the need for protecting groups, tedious functional group manipulations, and wasteful chromatography, which resulted in a greener process. This talk will emphasize how biocatalysis can be harnessed to provide unique advantages to the synthesis complex molecular targets such as MK-1454.
- |||||||||| ulevostinag (MK-1454) / Merck (MSD)
Journal: A Unified Strategy to Fluorinated Nucleoside Analogues Via an Electrophilic Manifold. (Pubmed Central) - Oct 25, 2022
Initially developed to facilitate the manufacture of 3'-fluoroguanosine (3'-FG)─a substructure of anticancer therapeutic MK-1454─this strategy has been extended to the synthesis of a variety of 3'-fluoronucleosides. Finally, we demonstrate the utility of the 2'-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), ulevostinag (MK-1454) / Merck (MSD)
Trial completion, Enrollment change, Trial completion date, Trial primary completion date, Monotherapy, Metastases: Study of Intratumoral (IT) Ulevostinag (MK-1454) in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002) (clinicaltrials.gov) - Oct 18, 2022
P2, N=18, Completed,
Finally, we demonstrate the utility of the 2'-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues. Active, not recruiting --> Completed | N=200 --> 18 | Trial completion date: Apr 2023 --> Sep 2022 | Trial primary completion date: Apr 2023 --> Sep 2022
- |||||||||| ulevostinag (MK-1454) / Merck (MSD), islatravir (MK-8591) / Merck (MSD), Lagevrio (molnupiravir) / Ridgeback Biotherap, Merck (MSD)
Review, Journal: Cascades of Evolved Enzymes for the Synthesis of Complex Molecules. (Pubmed Central) - Sep 23, 2022
This supports the goal of the chemical and pharmaceutical industries to move to more sustainable and environmentally friendly processes. Recently described outstanding examples include the biocatalytic cascade syntheses of the cyclic dinucleotide MK-1454, molnupiravir, and islatravir, as well as the efficient fixation of CO to make starch using an artificial enzyme cascade.
- |||||||||| ulevostinag (MK-1454) / Merck (MSD)
pH-switchable extractants for host cell protein rejection in the cascaded biocatalytic synthesis of an active pharmaceutical ingredient (W194a (McCormick Place Convention Center)) - Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_7032;
Leveraging the rapid generation of modular acid-base pairs, we describe a pH-coupled extraction strategy relying on tertiary ammonium extractant switches for efficient purification and isolation of hydrophilic immuno-oncology drug candidate MK-1454 from an aqueous biocatalytic cascade containing crude E. coli cell lysates. We demonstrate this technique on >300 g scale to isolate MK-1454 with no detectable protein impurities for human administration in clinical trials.
- |||||||||| ulevostinag (MK-1454) / Merck (MSD)
Journal: Holistic Analytical Characterization and Risk Assessment of Residual Host Cell Protein Impurities in an Active Pharmaceutical Ingredient (API) Synthesized by Biocatalysts. (Pubmed Central) - Jul 15, 2022
Although a lot of attentions have been focused on defining a universally acceptable limit for such impurities, the risks associated with residual HCPs on product quality, safety, and efficacy often need to be determined on a case-by-case basis taking into consideration the residual HCP profile in the product, the dose, dosage form, and administration route etc. Here we describe the unique challenges for residual HCP control presented by the biocatalytic synthesis of a Merck investigational stimulator of interferon genes protein (STING) agonist, MK-1454, which is a cyclic dinucleotide synthesized using E. coli cell lysate overexpressing cyclic GMP-AMP synthase (cGAS) as a biocatalyst. In this study, a holistic characterization of residual protein impurities using a variety of analytical tools including nano-LC-MS/MS, together with in silico immunogenicity prediction of identified proteins, facilitated risk assessment and guided process development to achieve adequate removal of residual protein impurities in MK-1454 API.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), ulevostinag (MK-1454) / Merck (MSD)
Trial completion, Enrollment change, Monotherapy, Metastases: Study of Ulevostinag (MK-1454) Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001) (clinicaltrials.gov) - Apr 25, 2022
P1, N=157, Completed,
In this study, a holistic characterization of residual protein impurities using a variety of analytical tools including nano-LC-MS/MS, together with in silico immunogenicity prediction of identified proteins, facilitated risk assessment and guided process development to achieve adequate removal of residual protein impurities in MK-1454 API. Active, not recruiting --> Completed | N=235 --> 157
- |||||||||| ulevostinag (MK-1454) / Merck (MSD)
Journal: A kinase-cGAS cascade to synthesize a therapeutic STING activator. (Pubmed Central) - Apr 19, 2022
P2
Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic (ClinicalTrials.gov study NCT04220866 )...For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules.
- |||||||||| ulevostinag (MK-1454) / Merck (MSD)
Journal: Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer. (Pubmed Central) - Apr 19, 2022
Tumor shrinkage in mouse models that are intrinsically resistant to single-agent therapy was further enhanced when treating the animals with MK-1454 in combination with a fully murinized antimouse PD-1 antibody, mDX400. These data support the development of STING agonists in combination with pembrolizumab (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 therapy.
- |||||||||| Welireg (belzutifan) / Merck (MSD), MK-1454 / Merck (MSD)
Accelerating drug discovery and development through Innovation in green chemistry (Room 1A (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_457;
The impact of such innovations is demonstrated in our recent development of a one-pot enzymatic process for the production of MK-1454, a stimulator of interferon gene (STING) protein agonist for the treatment of cancer, and in a commercial-scale photobromination in flow for the production of Belzutifan (MK-6482), an FDA-approved first-in-class therapy for the treatment of patients with Von Hippel-Lindau (VHL) disease-associated tumors. In both examples, innovation in green chemistry has dramatically improved the synthetic efficiency and reduced the waste generation.
- |||||||||| Review, Journal: Current status of intralesional agents in treatment of malignant melanoma. (Pubmed Central) - Jul 20, 2021
This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), ulevostinag (MK-1454) / Merck (MSD)
Trial completion date, Trial primary completion date, Monotherapy, Metastases: Study of Intratumoral (IT) Ulevostinag (MK-1454) in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002) (clinicaltrials.gov) - May 28, 2021
P2, N=200, Active, not recruiting,
Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents. Trial completion date: Sep 2023 --> Apr 2023 | Trial primary completion date: Sep 2023 --> Apr 2023
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), ulevostinag (MK-1454) / Merck (MSD)
Enrollment closed, Monotherapy, Metastases: Study of Intratumoral (IT) Ulevostinag (MK-1454) in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002) (clinicaltrials.gov) - Apr 19, 2021
P2, N=200, Active, not recruiting,
Recruiting --> Active, not recruiting Recruiting --> Active, not recruiting
- |||||||||| MK-1454 / Merck (MSD), ADU-S100 / Aduro BioTech, Novartis
Clinical, Review, Journal: The Age of Cyclic Dinucleotide Vaccine Adjuvants. (Pubmed Central) - Aug 24, 2020
P1, P2
Lately, the clinical trial from Aduro's CDN ADU-S100 monotherapy was also disappointing (NCT03172936)...Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), Erbitux (cetuximab) / Eli Lilly, EMD Serono, MK-1454 / Merck (MSD)
[VIRTUAL] Phase II study of intratumoral MK-1454 plus pembrolizumab compared with pembrolizumab monotherapy as first-line treatment for metastatic or unresectable, recurrent head and neck squamous cell carcinoma (On-Demand) - Jul 24, 2020 - Abstract #ESMO2020ESMO_1779;
P2
Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial identification: 2019-003060-42; NCT04220866.
- |||||||||| MK-1454 / Merck (MSD)
Characterization of STING pathway agonists using in vitro phenotypic assay models (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_2475;
A phase I clinical trial with a STING agonist (MK-1454) is currently underway in patients with advanced metastatic solid tumors or lymphomas...The effect on proliferation, apoptosis, and cell viability will be discussed. Tumor microenvironment models will also be treated with compounds and screened for validated biomarkers.
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