Chemoprotection and ALRN-6924

We are developing ALRN-6924 as a novel chemoprotective medicine to treat and protect healthy cells in patients with cancer that harbors p53-mutations to reduce or eliminate chemotherapy-induced side effects.

Scientific Publications

ALRN-6924

Pharmacological activation of p53 triggers viral mimicry response thereby abolishing tumor immune evasion and promoting anti-tumor immunity. X. Zhou, M. Singh, G.S. Santos, V. Guerlavais, L.A. Carvajal, M Aivado, Y. Zhan, M.M.S. Oliveira, L.S. Westerberg, D.A. Annis, J.I. Johnsen and G. Selivanova

Cancer Discovery, online ahead of print September 9, 2021 doi: 10.1158/2159-8290.CD-20-1741

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Article highlighted in The Scientist

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Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-Type TP53, M.N. Saleh, M.R. Patel, T.M. Bauer, S. Goel, G.S. Falchook, G.I. Shapiro, K.Y. Chung, J.R. Infante, R.M. Conry, G. Rabinowits, D.S. Hong, J.S. Wang, U. Steidl, G. Naik, V. Guerlavais, V. Vukovic, D.A. Annis, M. Aivado and F. Meric-Bernstam

Clin Cancer Res,  2021;27:5236–47

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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

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Article highlighted in The Hematologist

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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

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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

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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

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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

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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

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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.

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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

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Advancements in Stapled Peptide Drug Discovery & Development, V. Guerlavais, T. K. Sawyer.

Annual Reports in Medicinal Chemistry, Volume 49, 2014, 331–345.

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Macrocyclic α-helical peptide drug discovery, T. K. Sawyer, V. Guerlavais, K. Darlak, E. Feyfant.

RSC Drug Discovery Series No. 40, Macrocycles in Drug Discovery, 2014, chapter 9, 339-366.

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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

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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.

Proc Natl Acad Sci USA. 2013; 110(36):E3445-54

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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.

Cancer Cell. 18, 411-422 (2010).

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Article highlighted in Nature Reviews Drug Discovery

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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

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Scientific Events

2021 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

Poster Title: The Investigational Chemoprotection Drug ALRN-6924, a Dual Inhibitor of MDMX and MDM2, Shows Potential for Radioprotection

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2021 European Society of Medical Oncology (ESMO) Virtual Congress

Poster Title: A Phase 1b Study of the Dual MDMX/MDM2 Inhibitor, ALRN-6924, for the Prevention of Chemotherapy-induced Myelosuppression

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Poster Title: A Phase 1 Study of the Dual MDMX/MDM2 Inhibitor, ALRN 6924, in Healthy Volunteers

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2021 International Society for Experimental Hematology (ISEH) 50th Annual Scientific Meeting

Poster Title:ALRN-6924 is a Dual MDMX/MDM2 Inhibitor and Can Protect the Bone Marrow of Cancer Patients Treated with Chemotherapy

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2021 ASCO Annual Meeting

Poster Title: Gene Sequencing of Serial Tumor Biopsies from a Large Cohort of Cancer Patients Shows Longitudinal Changes in TP53 Mutation Status Are Uncommon

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2020 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

Poster Title: Prevention of Chemotherapy-induced Myelosuppression in SCLC Patients Treated with the Dual MDMX/MDM2 Inhibitor ALRN-6924

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2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

Poster title: The Investigational Peptide Drug ALRN-6924, a Dual Inhibitor of MDMX and MDM2, is an Effective Myelopreservation Agent

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2019 ESMO Congress

Poster title: ALRN-6924 and Palbociclib in Patients with MDM2 Amplified or MDM2/CDK4 Co-amplified Tumors: Interim Analysis

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2019 European Hematology Association (EHA) Congress

Poster title: ALRN-6924, a Dual Inhibitor of MDMX and MDM2 That Causes Minimal Thrombocytopenia in Patients, Disrupts Different Stages of Thrombopoiesis Compared to MDM2-only Inhibition

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2018 San Antonio Breast Cancer Symposium

Poster title: The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, and the CDK4/6 inhibitors palbociclib or abemaciclib synergistically enhance each other’s in vitro and in vivo anticancer activity.

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Poster title: The stapled peptide ALRN‐6924, a dual inhibitor of MDMX and MDM2, enhances antitumor efficacy of paclitaxel and Nab‐paclitaxel in TP53 wild‐type MCF‐7 breast cancer models.

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2018 ASH Annual Meeting And Exposition

Poster title: Preliminary Results of the Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Two Phase IIa Dose Expansion Cohorts in Relapsed/Refractory TP53 Wild-Type Peripheral T-Cell Lymphoma

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2018 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium

Poster title: Harnessing the anticancer activity of the stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, using rational combination strategies for breast cancer and other malignancies

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2018 Society For Immunotherapy Of Cancer (SITC) Annual Meeting

Poster title: The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, displays immunomodulatory activity and enhances immune checkpoint blockade in syngeneic mouse models

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2017 ASH Annual Meeting And Exposition

Presentation Title: In Vitro and Preclinical In Vivo Evidence Support MDMX/MDM2 as Common Vulnerabilities Across TP53-Wild-Type T-Cell Lymphomas That Are Targetable with the Alpha-Helical P53 Stapled Peptide ALRN-6924

Presentation Title: Dual Inhibition of MDMX and MDM2 Using an Alpha-Helical P53 Stapled Peptide (ALRN-6924) As a Novel Therapeutic Strategy in Acute Myeloid Leukemia

2017 ASCO Annual Meeting

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

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Abstract highlighted in Journal Clinical Oncology (ASCO Special article)

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Reviews

Macrocyclic Peptides

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

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

Reactivating p53

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

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

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.

Nature 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