Andrii Monastyrskyi, PhD

    The Monastyrskyi lab harnesses the power of organic chemistry and chemical biology to develop new tools for studying the function and therapeutic potential of cancer targets.          

Associations

• Drug Discovery
• Breast Oncology
• Neuro-Oncology
• Molecular Medicine Program

Education & Training

Graduate:

• University of South Florida, PhD - Organic Chemistry

Fellowship:

• The Scripps Research Institute - Chemistry

  Our laboratory uses the tools of synthetic organic chemistry, medicinal chemistry, and chemical biology to further develop small molecules for studying and modulating therapeutically relevant cancer targets. One aspect of current work focuses on the development of IND safety assessment candidates that inhibit the transcriptional kinases CDK12 and CDK13, the Wnt/beta-catenin regulators CK1d and CK1e, and the autophagy kinase ULK1. Further, developmental projects in the laboratory include campaigns to develop small molecules that disrupt key protein-protein interactions (e.g., those of Myc and Max) and RNA biogenesis.    

• Schmitz M, Kaltheuner IH, Anand K, Düster R, Moecking J, Monastyrskyi A, Duckett DR, Roush WR, Geyer M. The reversible inhibitor SR-4835 binds Cdk12/cyclin K in a noncanonical G-loop conformation. J Biol Chem. 2024 Jan.300(1):105501. Pubmedid: 38016516. Pmcid: PMC10767194.
• Morozova A, Chan SC, Bayle S, Sun L, Grassie D, Iermolaieva A, Kalaga MN, Frydman S, Sansil S, Schönbrunn E, Duckett D, Monastyrskyi A. Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties. Eur J Med Chem. 2024 Feb.266:116101. Pubmedid: 38232465.
• Liao Y, Remsing Rix LL, Li X, Fang B, Izumi V, Welsh EA, Monastyrskyi A, Haura EB, Koomen JM, Doebele RC, Rix U. Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2. Cell Chem Biol. 2024 Feb.31(2):284-297.e10. Pubmedid: 37848034. Pmcid: PMC10922442.
• Liao Y, Chin Chan S, Welsh EA, Fang B, Sun L, Schönbrunn E, Koomen JM, Duckett DR, Haura EB, Monastyrskyi A, Rix U. Chemical Proteomics with Novel Fully Functionalized Fragments and Stringent Target Prioritization Identifies the Glutathione-Dependent Isomerase GSTZ1 as a Lung Cancer Target. Acs Chem Biol. 2023 Feb.18(2):251-264. Pubmedid: 36630201.
• Burger KL, Fernandez MR, Meads MB, Sudalagunta PR, Oliveira PS, Renatino Canevarolo R, Alugubelli RR, Tungsevik A, De Avila G, Silva M, Graeter AI, Dai H, Vincelette ND, Prabhu A, Magaletti D, Yang C, Li W, Kulkarni A, Hampton OA, Koomen JM, Roush WR, Monastyrskyi A, Berglund AE, Silva AS, Cleveland JL, Shain KH. CK1δ and CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma. Cancer Res. 2023 Dec.83(23):3901-3919. Pubmedid: 37702657. Pmcid: PMC10690099.
• Nacheva K, Kulkarni SS, Kassu M, Flanigan D, Monastyrskyi A, Iyamu ID, Doi K, Barber M, Namelikonda N, Tipton JD, Parvatkar P, Wang HG, Manetsch R. Going beyond Binary: Rapid Identification of Protein-Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach. J Med Chem. 2023 Apr.66(7):5196-5207. Pubmedid: 37000900.
• Monastyrskyi A, Brockmeyer F, LaCrue AN, Zhao Y, Maher SP, Maignan JR, Padin-Irizarry V, Sakhno YI, Parvatkar PT, Asakawa AH, Huang L, Casandra D, Mashkouri S, Kyle DE, Manetsch R. Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1H)-Quinolones with Single Dose Cures. J Med Chem. 2021 May.64(10):6581-6595. Pubmedid: 33979164. Pmcid: PMC8904075.
• Tadesse S, Duckett DR, Monastyrskyi A. The promise and current status of CDK12/13 inhibition for the treatment of cancer. Future Med Chem. 2021 Jan.13(2):117-141. Pubmedid: 33295810.
• Maharaj K, Powers JJ, Achille A, Mediavilla-Varela M, Gamal W, Burger KL, Fonseca R, Jiang K, Miskin HP, Maryanski D, Monastyrskyi A, Duckett DR, Roush WR, Cleveland JL, Sahakian E, Pinilla-Ibarz J. The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv. 2020 Jul.4(13):3072-3084. Pubmedid: 32634240. Pmcid: PMC7362385.
• Vena F, Bayle S, Nieto A, Quereda V, Aceti M, Frydman SM, Sansil SS, Grant W, Monastyrskyi A, McDonald P, Roush WR, Teng M, Duckett D. Targeting Casein Kinase 1 Delta Sensitizes Pancreatic and Bladder Cancer Cells to Gemcitabine Treatment by Upregulating Deoxycytidine Kinase. Mol Cancer Ther. 2020 Aug.19(8):1623-1635. Pubmedid: 32430484. Pmcid: PMC7415672.
• Quereda V, Bayle S, Vena F, Frydman SM, Monastyrskyi A, Roush WR, Duckett DR. Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer. Cancer Cell. 2019 Nov.36(5):545-558.e7. Pubmedid: 31668947.
• Monastyrskyi A, Bayle S, Quereda V, Grant W, Cameron M, Duckett D, Roush W. Discovery of 2-arylquinazoline derivatives as a new class of ASK1 inhibitors. Bioorg Med Chem Lett. 2018 Feb.28(3):400-404. Pubmedid: 29277458. Pmcid: PMC5999544.
• Monastyrskyi A, Nilchan N, Quereda V, Noguchi Y, Ruiz C, Grant W, Cameron M, Duckett D, Roush W. Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer. Bioorg Med Chem. 2018 Feb.26(3):590-602. Pubmedid: 29289448. Pmcid: PMC5803353.
• Neelarapu R, Maignan JR, Lichorowic CL, Monastyrskyi A, Mutka TS, LaCrue AN, Blake LD, Casandra D, Mashkouri S, Burrows JN, Willis PA, Kyle DE, Manetsch R. Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies. J Med Chem. 2018 Feb.61(4):1450-1473. Pubmedid: 29215279. Pmcid: PMC6610884.
• Monastyrskyi A, Namelikonda NK, Manetsch R. Metal-free arylation of ethyl acetoacetate with hypervalent diaryliodonium salts: an immediate access to diverse 3-aryl-4(1H)-quinolones. J Org Chem. 2015 Mar.80(5):2513-2520. Pubmedid: 25558982. Pmcid: PMC4479256.
• Monastyrskyi A, Kyle DE, Manetsch R. 4(1H)-pyridone and 4(1H)-quinolone derivatives as antimalarials with erythrocytic, exoerythrocytic, and transmission blocking activities. Curr Top Med Chem. 2014 Sep.14(14):1693-1705. Pubmedid: 25116582. Pmcid: PMC4479281.
• Cross RM, Flanigan DL, Monastyrskyi A, LaCrue AN, Sáenz FE, Maignan JR, Mutka TS, White KL, Shackleford DM, Bathurst I, Fronczek FR, Wojtas L, Guida WC, Charman SA, Burrows JN, Kyle DE, Manetsch R. Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium. J Med Chem. 2014 Nov.57(21):8860-8879. Pubmedid: 25148516. Pmcid: PMC4234439.
• Lacrue AN, Sáenz FE, Cross RM, Udenze KO, Monastyrskyi A, Stein S, Mutka TS, Manetsch R, Kyle DE. 4(1H)-Quinolones with liver stage activity against Plasmodium berghei. Antimicrob Agents Chemother. 2013 Jan.57(1):417-424. Pubmedid: 23129047. Pmcid: PMC3535941.
• Cross RM, Monastyrskyi A, Mutka TS, Burrows JN, Kyle DE, Manetsch R. Endochin optimization: structure-activity and structure-property relationship studies of 3-substituted 2-methyl-4(1H)-quinolones with antimalarial activity. J Med Chem. 2010 Oct.53(19):7076-7094. Pubmedid: 20828199.

• Title: Integrated Fragment-Based Phenotypic Screening and Chemoproteomics for Identification of Novel Small Cell Lung Cancer-Specific Targets
  Sponsor: Nat Institutes of Health
  PI (Contact): Rix, U., PI (MPI): Monastyrskyi, A.
• Title: Harnessing CDK12 inhibition for the treatment of HER2+ brain metastatic breast cancers
  Sponsor: US Army
  PI: Monastyrskyi, A.
• Title: Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers supplement
  Sponsor: Nat Institutes of Health
  PI (Contact): Duckett, D., PI: Monastyrskyi, A.
• Title: Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers
  Sponsor: Nat Institutes of Health
  PI (Contact): Duckett, D., PI: Monastyrskyi, A., PI: Haura, E.