5 results on '"Jay Larrow"'
Search Results
2. Targeted degradation of IKZF2 for cancer immunotherapy
- Author
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Jonathan Solomon, Simone Bonazzi, Eva d'Hennezel, Rohan Beckwith, Lei Xu, Aleem Fazal, Anna Magracheva, Radha Ramesh, Artiom Cernijenko, Brandon Antonakos, Hyo-eun Bhang, Roxana Garcia Caro, Jennifer Cobb, Elizabeth Ornelas, Xiaolei Ma, Charles Wartchow, Matt Clifton, Ry Forseth, Bethany Fortnam, Hongbo Lu, Alfredo Csibi, Jennifer Tullai, Seth Carbonneau, Noel Thomsen, Jay Larrow, Barbara Chie-Leon, Dominik Hainzl, Yi Gu, Darlene Lu, Matthew Meyer, Dylan Alexander, Jacqueline Kinyamu-Akunda, Catherine Sabatos-Peyton, Natalie Dales, Frederic Zecri, Rishi Jain, Janine Shulok, Y. Karen Wang, Karin Briner, Jeffrey Porter, John Tallarico, Jeffrey Engelman, Glenn Dranoff, Jay Bradner, and Michael Visser
- Abstract
Growing malignant tumors must evade destruction by the immune system, a hurdle some malignancies overcome by attracting immune-suppressive regulatory T-cells (Tregs)1. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Tregs, and IKZF2 deficiency enhances immune responses to tumors in mice2, suggesting IKZF2 may be an attractive target for cancer immunotherapy. Here we describe the discovery and characterization of DKY709, the first molecular glue degrader of IKZF2/4 which spares IKZF1/3. DKY709 was identified through a recruitment-guided medicinal chemistry campaign that redirected the degradation selectivity of CRBN binders towards IKZF2. The IKZF transcription factor selectivity of DKY709 was rationalized by the X-ray structure of the CRBN-DKY709-IKZF2(ZF2) ternary complex. Upon exposure to DKY709, human Tregs showed reduced suppressive activity and exhausted T-effector cells recovered IFNγ production. In vivo, oral treatment with DKY709 drove a rapid and sustained degradation of IKZF2 including in humans and led to delayed tumor growth in mice with humanized immune systems and enhanced immunization responses in monkeys. DKY709 is a first-in-class, potent and selective oral IKZF2/4 degrader currently being investigated in a phase 1 clinical trial as an immune-enhancing agent for cancer immunotherapy.
- Published
- 2022
3. Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
- Author
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Matthew J. LaMarche, Peter Fekkes, Jorge Garcia Fortanet, Michael Shultz, Denise Grunenfelder, Zhouliang Chen, Gang Liu, Chen Christine Hiu-Tung, Minying Pu, Travis Stams, Pascal D. Fortin, Palermo Mark G, Ping Wang, Samuel B. Ho, Brant Firestone, Matthew J. Meyer, Dyuti Majumdar, Laura R. LaBonte, Francois Lenoir, Rajesh Karki, Nick Keen, Cary Fridrich, Michelle Fodor, Jay Larrow, Sarah Williams, Christopher Towler, Timothy Michael Ramsey, Ji-Hu Zhang, Franco Lombardo, Ying-Nan P. Chen, Zhan Deng, Mitsunori Kato, Zhao B. Kang, Lawrence Blas Perez, Shumei Liu, and William R. Sellers
- Subjects
Male ,Models, Molecular ,0301 basic medicine ,Programmed cell death ,Allosteric modulator ,Protein Conformation ,Allosteric regulation ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Crystallography, X-Ray ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Protein structure ,Allosteric Regulation ,Piperidines ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Chemistry ,Small molecule ,High-Throughput Screening Assays ,Mice, Inbred C57BL ,PTPN11 ,Pyrimidines ,030104 developmental biology ,Biochemistry ,Drug Design ,Pyrazines ,030220 oncology & carcinogenesis ,Heterografts ,Molecular Medicine ,Female ,Allosteric Site ,Neoplasm Transplantation - Abstract
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
- Published
- 2016
4. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases
- Author
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Palermo Mark G, Timothy Michael Ramsey, Ping Zhu, Shumei Liu, Jay Larrow, Laura R. La Bonte, Rajesh Karki, Chen Christine Hiu-Tung, Kavitha Venkatesan, Jaison Jacob, Pascal D. Fortin, Francois Lenoir, Hui Gao, Guizhi Yang, Matthew J. Meyer, Ji-Hu Zhang, William R. Sellers, Michael Shultz, Denise Grunenfelder, Edmund Price, Jorge Garcia-Fortanet, Feng Fei, Zhouliang Chen, Gang Liu, Vesselina G. Cooke, Jing Yuan, Michelle Fodor, Ping Wang, Minying Pu, Nicholas Keen, Samuel B. Ho, Kathy Hsiao, Markus Warmuth, Travis Stams, Christopher Quinn, Mitsunori Kato, Subarna Shakya, Sarah Williams, Dyuti Majumdar, Peter Fekkes, Michael G. Acker, Cary Fridrich, Joanna Slisz, Huaixiang Hao, Matthew J. LaMarche, Ying-Nan P. Chen, Brandon Antonakos, Jason R. Dobson, Brant Firestone, Lawrence Blas Perez, Zhao B. Kang, Ho Man Chan, and Zhan Deng
- Subjects
0301 basic medicine ,Multidisciplinary ,biology ,Cell growth ,Protein tyrosine phosphatase ,Receptor tyrosine kinase ,Immune checkpoint ,Cell biology ,PTPN11 ,03 medical and health sciences ,030104 developmental biology ,Growth factor receptor ,biology.protein ,Signal transduction ,Tyrosine - Abstract
SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models. The tyrosine phosphatase SHP2 is a key mediator of receptor tyrosine kinase (RTK) signalling, as well as being important in immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth, and SHP2 is a potential, but so far elusive, therapeutic target in cancer. Pascal Fortin and colleagues report the development of a selective SHP2 inhibitor with drug-like properties. The inhibitor, SHP099, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation. It also suppresses RAS–ERK signalling to inhibit RTK-driven proliferation in human cancer cell lines and mouse tumour xenograft models. The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase1. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma1,2,3,4,5. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2,3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways6,7. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy8,9. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
- Published
- 2016
5. Abstract 2084: Conformational activation and allosteric inhibition of SHP2 in RTK-driven cancers
- Author
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Kavitha Venkatesan, Jaison Jacob, Shumei Liu, Fei Feng, Brandon Antonakos, Zhao B. Kang, Jonathan R. LaRochelle, Jason R. Dobson, Hui Gao, Laura R. La Bonte, Huaixiang Hao, Rajesh Karki, Samuel B. Ho, Guizhi Yang, Markus Warmuth, Ping Zhu, Matthew J. LaMarche, Brant Firestone, Matthew J. Meyer, Stephen C. Blacklow, Edmund Price, Kathy Hsiao, Jorge Garcia-Fortanet, Zhuoliang Chen, Chen Christine Hiu-Tung, Palermo Mark G, Vesselina G. Cooke, Cary Fridrich, Jay Larrow, Ping Wang, Sarah Williams, Ying-Nan P. Chen, Subarna Shakya, William R. Sellers, Nicholas Keen, Jing Yuan, Michael Shultz, Gang Liu, Michelle Fodor, Michael G. Acker, Pascal D. Fortin, Ho Man Chan, Timothy Michael Ramsey, Zhan Deng, Ji-Hu Zhang, Mitsunori Kato, Dyuti Majumdar, Peter Fekkes, Minying Pu, and Travis Stams
- Subjects
Cancer Research ,biology ,Philosophy ,Allosteric regulation ,Cancer therapy ,Protein tyrosine phosphatase ,medicine.disease ,Mapk signaling ,Oncology ,Allosteric enzyme ,Neuroblastoma ,Cancer research ,medicine ,biology.protein ,Tumor growth ,Majumdar - Abstract
The non-receptor protein tyrosine phosphatase (PTP) SHP2 is an important component of RTK signaling in response to growth factor stimulus and sits just upstream of the RAS-MAPK signaling cascade. The first oncogenic phosphatase to be identified, SHP2 is dysregulated in multiple human diseases including the developmental disorders Noonan and Leopard syndromes, as well as leukemia, lung cancer and neuroblastoma where aberrant activity of SHP2 leads to uncontrolled MAPK signaling. Cancer-associated activating mutations in SHP2 impart an “auto-on” state of the enzyme, boosting basal activity by shifting the equilibrium away from the auto-inhibited state. Reduction of SHP2 activity through genetic knockdown suppresses tumor growth, validating SHP2 as a target for cancer therapy. SHP099, a recently reported potent and selective allosteric inhibitor of SHP2, stabilizes the auto-inhibited form of SHP2 through interactions with the N-terminal SH2 and C-terminal PTP domains of the protein. SHP099 suppresses MAPK signaling in RTK amplified cancers resulting in suppressed proliferation in vitro and inhibition of tumor growth in mouse tumor xenograft models. Together, these data demonstrate the therapeutic potential of SHP2 inhibition in the treatment of cancer and other RAS/MAPK-linked diseases. Citation Format: Michael G. Acker, Ying-Nan P. Chen, Matthew J. LaMarche, Ho Man Chan, Peter Fekkes, Jorge Garcia-Fortanet, Jonathan R. LaRochelle, Brandon Antonakos, Christine Hiu-Tung Chen, Zhuoliang Chen, Vesselina G. Cooke, Jason R. Dobson, Zhan Deng, Fei Feng, Brant Firestone, Michelle Fodor, Cary Fridrich, Hui Gao, Huai-Xiang Hao, Jaison Jacob, Samuel Ho, Kathy Hsiao, Zhao B. Kang, Rajesh Karki, Mitsunori Kato, Jay Larrow, Laura R. La Bonte, Gang Liu, Shumei Liu, Dyuti Majumdar, Matthew J. Meyer, Mark Palermo, Minying Pu, Edmund Price, Subarna Shakya, Michael D. Shultz, Kavitha Venkatesan, Ping Wang, Markus Warmuth, Sarah Williams, Guizhi Yang, Jing Yuan, Ji-Hu Zhang, Ping Zhu, Stephen C. Blacklow, Timothy Ramsey, Nicholas J. Keen, William R. Sellers, Travis Stams, Pascal D. Fortin. Conformational activation and allosteric inhibition of SHP2 in RTK-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2084. doi:10.1158/1538-7445.AM2017-2084
- Published
- 2017
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