Science

We believe that stabilized cell-permeating peptide therapeutics have the potential to become a major class of drugs for oncology and other diseases.

Scientific Publications

ALRN-6924

Dual inhibition of MDMX and MDM2 as a Therapeutic Strategy in Leukemia, A. Carvajal, D. Ben Neriah, A. Senecal, L. Benard, V. Thiruthuvanathan, T. Yatsenko, S.-R. Narayanagari, J. C. Wheat, T. I. Todorova, K. M. Mitchell, C. Kenworthy, V. Guerlavais, D. A. Annis, B. Bartholdy, Britta Will, J. D. Anampa, I. Mantzaris, M. Aivado, R. H. Singer, R. A. Coleman, A.Verma, U. Steidl. Sci Transl Med. 2018, 10(436). pii: eaao3003

https://stm.sciencemag.org/content/10/436/eaao3003/tab-pdf

Article highlighted in The Hematologist

https://www.hematology.org/Thehematologist/Diffusion/8673.aspx

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models, S. Y. Ng, N. Yoshida, A. L. Christie, M. Ghandi, N. V. Dharia, J. Dempster, M. Murakami, K. Shigemori, S. N. Morrow, A. Van Scoyk, N. A. Cordero, K. E. Stevenson, M. Puligandla, B. Haas, C. Lo, R. Meyers, G. Gao, A. Cherniack, A. Louissaint JR, V. Nardi, A. R. Thorner, H. Long, X. Qiu, E. A. Morgan, D. M. Dorfman, D. Fiore, J. Jang, A. L. Epstein, A. Dogan, Y. Zhang, S. M. Horwitz, E. D. Jacobsen, S. Santiago, J.-G. Ren, Guerlavais, D. A. Annis, M. Aivado, M. N. Saleh, A. Mehta, A. Tsherniak, D. Root, F. Vazquez, W. C. Hahn, G. Inghirami, J. C. Aster, D. M. Weinstock, R. Koch, Nat Commun. 2018, 22, 9(1) : 2024 https://www.nature.com/articles/s41467-018-04356-9

Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas

Funda Meric-Bernstam, Mansoor N. Saleh, Jeffrey R. Infante, Sanjay Goel, Gerald Steven Falchook, Geoffrey Shapiro, Ki Y Chung, Robert Martin Conry, David S. Hong, Judy Sing-Zan Wang, Ulrich Steidl, Loren D. Walensky, Vincent Guerlavais, Marie Payton, D. Allen Annis, Manuel Aivado, and Manish R. Patel. Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas. J of Clin Oncol. 35:15_suppl, 2505-2505 (2017)

https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2505
https://investors.aileronrx.com/static-files/1bd4ccdb-c057-4aea-a83f-9076761ba416

Abstract highlighted in Journal Clinical Oncology (ASCO Special article)

https://ascopubs.org/doi/pdf/10.1200/JCO.2017.77.0446

MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors. Howard TP, Arnoff TE, Song MR, Giacomelli AO, Wang X, Hong AL, Dharia NV, Wang S, Vazquez F, Pham MT, Morgan AM, Wachter F, Bird GH, Kugener G, Oberlick EM, Rees MG, Tiv HL, Hwang JH, Walsh KH, Cook A, Krill-Burger JM, Tsherniak A, Gokhale PC, Park PJ, Stegmaier K, Walensky LD, Hahn WC, Roberts CWM. Cancer Res. 2019 ;79(9):2404-2414

http://cancerres.aacrjournals.org/content/79/9/2404.long

Spatial Profiling of Stapled α–helical Peptide Atsp-7041 In Mouse Whole-body Thin Tissue Sections Using Droplet-based Liquid Microjunction Surface Sampling-hplc-esi–ms/ms, V Kertesz, M Vavrek, C Freddo, G J Van Berkel, International Journal of Mass Spectrometry, 2019, 437, 17-22

https://www.sciencedirect.com/science/article/pii/S138738061730355X

Macrocyclic α helical peptide therapeutic modality: A perspective of learnings and challenges, Sawyer TK, Partridge AW, Kaan HYK, Juang YC, Lim S, Johannes C, Yuen TY, Verma C, Kannan S, Aronica P, Tan YS, Sherborne B, Ha S, Hochman J, Chen S, Surdi L, Peier A, Sauvagnat B, Dandliker PJ, Brown CJ, Ng S, Ferrer F, Lane DP. Bioorg Med Chem. 2018 ; 26(10) :2807-2815

https://www.sciencedirect.com/science/article/pii/S0968089618301743?via%3Dihub

Genome-scale CRI SPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma. Stolte, A. Balboni Iniguez, N. V. Dharia, A. L. Robichaud, Amy Saur Conway, Ann M. Morgan, G. Alexe, N. J. Schauer, X. Liu, G. H. Bird, A. Tsherniak, F. Vazquez, S J. Buhrlage, L D. Walensky, and K Stegmaier. J Exp Med. 2018 ;215(8):2137-2155

http://jem.rupress.org/content/215/8/2137.long

Designing dual inhibitors of Mdm2/MdmX: Unexpected coupling of water with gatekeeper Y100/99. Lee XA, Verma C, Sim AYL. 2017 ;85(8):1493-1506

https://onlinelibrary.wiley.com/doi/abs/10.1002/prot.25310

Mechanistic validation of a clinical lead stapled peptide that reactivates p53 by dual HDM2 and HDMX targeting. Wachter F, Morgan AM, Godes M, Mourtada R, Bird GH, Walensky LD. Oncogene 2017 ;36(15):2184-2190.

https://www.nature.com/articles/onc2016361

Toward Understanding the Molecular Recognition of Albumin by p53-Activating Stapled Peptide ATSP-7041. Tiwari G, Verma CS. J Phys Chem B. 2017 ;121(4):657-670

https://pubs.acs.org/doi/10.1021/acs.jpcb.6b09900

Advancements in Stapled Peptide Drug Discovery & Development, Guerlavais, T. K. Sawyer, Annual Reports in Medicinal Chemistry, Volume 49, 2014, 331–345.

https://www.sciencedirect.com/science/article/pii/B9780128001677000213

Macrocyclic α-helical peptide drug discovery, K. Sawyer, V. Guerlavais, K. Darlak, E. Feyfant, RSC Drug Discovery Series No. 40, Macrocycles in Drug Discovery, 2014, chapter 9, 339-366.

https://pubs.rsc.org/en/content/chapter/bk9781849737012-00339/978-1-84973-701-2

Design, Synthesis, Biophysical and Structure-Activity Properties of a Novel Dual MDM2 and MDMX Targeting Stapled α-Helical Peptide: ATSP-7041 Exhibits Potent In Vitro and In Vivo Efficacy in Xenograft Models of Human Cancer. Guerlavais, K. Darlak, B. Graves, C. Tovar, K. Packman, K. Olson, K. Kesavan, P. Gangurde, J. Horstick, A. Mukherjee, T. Baker, X.E. Shi, S. Lentini, K. Sun, S. Irwin, E. Feyfant, T. To, Z. Filipovic, C. Elkin, J. Pero, S. Santiago, T. Bruton, T. Sawyer, A. Annis, N. Fotouhi, T. Manning, H. Nash, L.T. Vassilev, Y.S. Chang and T.K. Sawyer. Proceedings of the 23rd American Peptide symposium, American Peptide Society, 2013, 217-218

https://www.americanpeptidesociety.org/assets/pdf-files/proceedings/23.pdf

Stapled α-helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Chang, Y.S., Graves, B., Guerlavais, V., Tovar, C., Packman, K., To, K. -H., Olson, K. A., Kesavan, K., Gangurde, P., Mukherjee, A., Baker, T., Darlak, K., Elkin, C., Filipovic, Z., Qureshi, F. Z., Cai, H., Berry, P., Feyfant, E., Shi, X. E., Horstick, J., Annis, D. A., Manning, A. M., Fotouhi, N., Nash, H., Vassilev, L. T. & Sawyer, T. K. Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci USA. 2013; 110(36):E3445-54.
http://www.pnas.org/content/early/2013/08/13/1303002110.full.pdf

A stapled p53 helix overcomes HDMX-mediated suppression of p53. Bernal, F., Wade, M., Godes, M., Davis, T. N., Whitehead, D. G., Kung, A. L., Wahl, G.M. & Walensky, L. D. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell. 18, 411-422 (2010).

https://www.cell.com/action/showPdf?pii=S1535-6108%2810%2900426-5

Article highlighted in Nature Reviews Drug Discovery http://www.nature.com/nrd/journal/v10/n1/full/nrd3342.html

Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. Bernal F, Tyler AF, Korsmeyer SJ, Walensky LD, Verdine GL. J Am Chem Soc. 2007 Mar 7;129(9):2456-7

https://pubs.acs.org/doi/abs/10.1021/ja0693587




Reviews

Macrocyclic Peptides as PPI inhibitors

Cyclic peptide therapeutics: past, present and future. A. Zorzi, K. Deyle, Heinis, Current Opinion in Chemical Biology 2017, 38:24–29

https://www.sciencedirect.com/science/article/abs/pii/S1367593116302010?via%3Dihub

Stabilized helical peptides: overview of the technologies and its impact on drug discovery, Mark Klein. Expert Opinion on Drug Discovery, 2017, 12:11, 1117-1125

https://www.tandfonline.com/doi/abs/10.1080/17460441.2017.1372745?journalCode=iedc20

Protein epitope mimetic macrocycles as biopharmaceuticals, Luther A, Moehle K, Chevalier E, Dale G, Obrecht D. Curr Opin Chem Biol. 2017 ;38:45-51

https://www.sciencedirect.com/science/article/abs/pii/S1367593116301934?via%3Dihub

Peptides and peptidomimetics as regulators of protein-protein interactions. Cunningham AD, Qvit N, Mochly-Rosen D. Curr Opin Struct Biol. 2017; 44:59-66

https://www.sciencedirect.com/science/article/abs/pii/S0959440X16301300?via%3Dihub

New Modalities for Challenging Targets in Drug Discovery. Valeur E, Guéret SM, Adihou H, Gopalakrishnan R, Lemurell M, Waldmann H, Grossmann TN, Plowright AT. Angew Chem Int Ed Engl. 2017 ;56(35):10294-10323.

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201611914

Reactivating p53 Tumor Suppressor

Impact of oncogenic pathways on evasion of antitumour immune responses, Spranger S, Gajewski TF, Nat Rev Cancer. 2018 ;18(3):139-147

https://www.nature.com/articles/nrc.2017.117

Exploiting the p53 Pathway for Therapy. Cheok CF, Lane D. Cold Spring Harb Perspect Med. 2017;7(3). pii: a026310).

http://perspectivesinmedicine.cshlp.org/content/7/3/a026310.long

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment. Cui Y, Guo G. Int J Mol Sci. 2016 ;17(11)

https://www.mdpi.com/1422-0067/17/11/1942

Emerging roles of p53 and other tumour-suppressor genes. Muñoz-Fontela C, Mandinova A, Aaronson SA, Lee SW. Nat Rev Immunol. 2016;16(12):741-750

https://www.nature.com/articles/nri.2016.99

MDMX (MDM4), a Promising Target for p53 Reactivation Therapy and Beyond, JC Marine, A. Jochemsen, Cold Spring Harb Perspect Med. 2016;6(7). pii: a026237

http://perspectivesinmedicine.cshlp.org/content/6/7/a026237.long

The Role of MDM2 Amplification and Overexpression in Tumorigenesis. Oliner JD, Saiki AY, Caenepeel S. Cold Spring Harb Perspect Med. 2016 ;6(6). pii: a026336.

http://perspectivesinmedicine.cshlp.org/content/6/6/a026336.long

Clinical Overview of MDM2/X-Targeted Therapies. Burgess A, Chia KM, Haupt S, Thomas D, Haupt Y, Lim E. Front Oncol. 2016 ;6:7.

https://www.frontiersin.org/articles/10.3389/fonc.2016.00007/full

The Roles of MDM2 and MDMX in Cancer, O. Karni-Schmidt, M. Lokshin, C. Prives, Annu. Rev. Pathol. Mech. Dis. 2016 11:617-44

https://www.annualreviews.org/doi/abs/10.1146/annurev-pathol-012414-040349?rfr_dat=cr_pub%3Dpubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&journalCode=pathmechdis

p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Kruiswijk F, Labuschagne CF, Vousden KH, Nat Rev Mol Cell Biol. 2015 ;16(7):393-405

https://www.nature.com/articles/nrm4007

Unravelling mechanisms of p53-mediated tumour suppression. Bieging KT, Mello SS, Attardi LD, Nat Rev Cancer. 2014 ;14(5):359-70.

https://www.nature.com/articles/nrc3711

MDM2, MDMX and p53 in oncogenesis and cancer therapy. Wade M, Li YC, Wahl GM. Reviews Cancer. 2013;13(2):83-96.

https://www.nature.com/articles/nrc3430

Translating p53 into the clinic. Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. Nature Reviews Clinical Oncology. 2011;8(1):25-37

https://www.nature.com/articles/nrclinonc.2010.174