This phase I/Ib trial tests the side effects, best dose, tolerability, and effectiveness of RMC-5552 in treating patients with glioblastoma that has come back (recurrent). RMC-5552 is a type of medicine called an mechanistic target of rapamycin (mTOR) inhibitor. These types of drugs prevent the formation of a specific group of proteins called mTOR. This protein controls cancer cell growth, and the study doctors believe stopping mTOR from forming may help to kill tumor cells.

开始日期2023-04-03

申办/合作机构

The University of California, San Francisco

[+2]

NCT04774952 / Active, not recruiting临床1期

A Phase 1/1b, Open-Label, Multicenter, Dose-Escalation Study of RMC 5552 Monotherapy in Adult Subjects With Relapsed/Refractory Solid Tumors

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of escalating doses of RMC-5552 monotherapy in adult participants with relapsed/refractory solid tumors and to identify the recommended Phase 2 dose (RP2D).

开始日期2021-04-07

申办/合作机构

Revolution Medicines, Inc.

100 项与 RMC-5552 相关的临床结果

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100 项与 RMC-5552 相关的转化医学

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100 项与 RMC-5552 相关的专利（医药）

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项与 RMC-5552 相关的文献（医药）

2024-01-01·Neuro-oncology advances

Preclinical evaluation of the third-generation, bi-steric mechanistic target of rapamycin complex 1-selective inhibitor RMC-6272 in NF2-deficient models

Article

作者: Kosa, Lili ; Chang, Long-Sheng ; Ramesh, Vijaya ; Bhattacharyya, Srirupa ; Plotkin, Scott R ; Beauchamp, Roberta L ; Oblinger, Janet L ; Robert, Francis

Abstract:

Background:

NF2-associated meningiomas are progressive, highly morbid, and nonresponsive to chemotherapies, highlighting the need for improved treatments. We have established aberrant activation of the mechanistic target of rapamycin (mTOR) signaling in NF2-deficient tumors, leading to clinical trials with first- and second-generation mTOR inhibitors. However, results have been mixed, showing stabilized tumor growth without shrinkage offset by adverse side effects. To address these limitations, here we explored the potential of third-generation, bi-steric mTOR complex 1 (mTORC1) inhibitors using the preclinical tool compound RMC-6272.

Methods:

Employing human NF2-deficient meningioma lines, we compared mTOR inhibitors rapamycin (first-generation), INK128 (second-generation), and RMC-6272 (third-generation) using in vitro dose–response testing, cell-cycle analysis, and immunoblotting. Furthermore, the efficacy of RMC-6272 was assessed in NF2-null 3D-spheroid meningioma models, and its in vivo potential was evaluated in 2 orthotopic meningioma mouse models.

Results:

Treatment of meningioma cells revealed that, unlike rapamycin, RMC-6272 demonstrated superior growth inhibitory effects, cell-cycle arrest, and complete inhibition of phosphorylated 4E-BP1 (mTORC1 readout). Moreover, RMC-6272 had a longer retention time than INK128 and inhibited the expression of several eIF4E-sensitive targets on the protein level. RMC-6272 treatment of NF2 spheroids showed significant shrinkage in size as well as reduced proliferation. Furthermore, in vivo studies in mice revealed effective blockage of meningioma growth by RMC-6272, compared with vehicle controls.

Conclusions:

Our study in preclinical models of NF2 supports possible future clinical evaluation of third-generation, investigational mTORC1 inhibitors, such as RMC-5552, as a potential treatment strategy for NF2.

2023-01-12·Journal of medicinal chemistry1区 · 医学

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors

1区 · 医学

Article

作者: Tzitzilonis, Christos ; Zhao, Yongyuan ; Choi, Jong S. ; Cregg, James ; Lee, Julie C. ; Marquez, Abby ; Kiss, Gert ; Knox, John E. ; Smith, Jacqueline A. M. ; Thottumkara, Arun P. ; Burnett, G. Leslie ; Singh, Mallika ; Jiang, Jingjing ; Lee, Bianca J. ; Aggen, James B. ; Gliedt, Micah K. ; Wang, Zhican ; Yang, Yu C. ; Meyerowitz, Justin G. ; Won, Walter S. ; Evans, James W. ; Pitzen, Jennifer ; Semko, Chris M. ; Mellem, Kevin T. ; Gill, Adrian L. ; Wildes, David ; Wang, Zhengping ; Tomlinson, Aidan C. A. ; Wang, Gang

Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS^G12C shows increased antitumor activity in a preclinical model of KRAS^G12C mutant NSCLC that exhibits resistance to KRAS^G12C inhibitor monotherapy.

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY

The Bi-Steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis

Article

作者: Mukhitov, Alexander R ; Basil, Maria C. ; Rue, Ryan ; Evans, Jilly F. ; Kanth, Swaroop V. ; Henske, Elizabeth P ; Tang, Yan ; Krymskaya, Vera P ; Ledwell, Owen A. ; Cantu, Edward ; Diesler, Rémi ; Lin, Susan M.

Mutations in the Tuberous Sclerosis Complex (TSC) genes result in the hyperactivation of the mechanistic/mammalian target of rapamycin 1 (mTORC1) growth pathway in mesenchymal pulmonary cells. Rapamycin (Sirolimus^TM), a naturally occurring macrolide, is the only therapeutic approved for women with lymphangioleiomyomatosis (LAM), a progressive, destructive lung disease caused by TSC gene mutations and mTORC1 hyperactivation. However, on cessation of the drug, lung function decline continues. We demonstrated here that pulmonary LAM cancer stem-like cells (SLS) most highly expressed the eukaryotic translation initiation factor 4E (eIF4E)-dependent translation initiation genes. We also showed that the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) gene has the lowest expression in these cells, indicating that the 4E-BP1/eIF4E ratio in LAM SLS cells favors unrestrained eIF4E oncogenic mRNA translation. The bi-steric mTORC1-selective compound RMC-5552 prevented growth of LAM-associated fibroblasts (LAFs) and phosphorylation of proteins in the ribosomal protein S6K1/ribosomal protein S6 (S6K1/S6) and 4E-BP1/eIF4E translation mTORC1-driven pathways, whereas rapamycin only blocked the S6K/S6 axis. Rapamycin inhibition of LAF growth was rapidly reversed, but RMC-5552 inhibition was more durable. RMC-5552, through its potential to eradicate LAM cancer SLS cells, may have therapeutic benefit in LAM and other diseases with mTORC1 hyperactivity.

项与 RMC-5552 相关的新闻（医药）

2024-12-05

·GlobeNewswire-Health Care

Revolution Medicines Announces Closing of Upsized Public Offering of Common Stock and Pre-Funded Warrants and Full Exercise of Underwriters' Option to Purchase Additional Shares

Underwriters’ full exercise of option brings gross proceeds to $862.5 millionREDWOOD CITY, Calif., Dec. 05, 2024 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, today announced the closing of its underwritten public offering of 16,576,088 shares of its common stock at a public offering price of $46.00 per share, before underwriting discounts and commissions, and, in lieu of shares of common stock, to certain investors, pre-funded warrants to purchase 2,173,917 shares of common stock at a public offering price of $45.9999, which represents the per share public offering price for the common stock less the $0.0001 per share exercise price for each pre-funded warrant. The shares of common stock issued and sold in the offering include 2,445,652 shares issued upon exercise in full by the underwriters of their option to purchase additional shares of common stock at the public offering price, less underwriting discounts and commissions. The gross proceeds from the offering, before deducting underwriting discounts and commissions and other offering expenses payable by Revolution Medicines, were $862.5 million. All shares and pre-funded warrants in the offering were offered by Revolution Medicines. J.P. Morgan, TD Cowen, Goldman Sachs & Co. LLC and Guggenheim Securities acted as joint book-running managers for the offering. UBS Investment Bank acted as lead manager. A shelf registration statement relating to these securities was filed with the U.S. Securities and Exchange Commission (SEC) on March 4, 2024, and automatically became effective upon filing. This offering was made solely by means of a prospectus. A copy of the final prospectus supplement and the accompanying prospectus relating to this offering may be obtained for free by visiting EDGAR on the SEC’s website at www.sec.gov. Alternatively, a copy of the final prospectus supplement and the accompanying prospectus relating to this offering may be obtained by contacting: J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York 11717, by email at prospectus-eq_fi@jpmchase.com and postsalemanualrequests@broadridge.com; TD Securities (USA) LLC, 1 Vanderbilt Avenue, New York, New York 10017, by telephone at (855) 495-9846 or by email at TD.ECM_Prospectus@tdsecurities.com; Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, by telephone at (866) 471-2526 or by email at prospectus-ny@ny.email.gs.com; and Guggenheim Securities, LLC, Attention: Equity Syndicate Department, 330 Madison Avenue, 8th Floor, New York, New York 10017, by telephone at (212) 518-9544 or by email at GSEquityProspectusDelivery@guggenheimpartners.com. This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction. About Revolution Medicines, Inc. Revolution Medicines is a clinical-stage oncology company developing novel targeted therapies for RAS-addicted cancers. The company’s R&D pipeline comprises RAS(ON) inhibitors designed to suppress diverse oncogenic variants of RAS proteins. The company’s RAS(ON) inhibitors RMC-6236, a RAS(ON) multi-selective inhibitor, RMC-6291, a RAS(ON) G12C-selective inhibitor, and RMC-9805, a RAS(ON) G12D-selective inhibitor, are currently in clinical development. Additional development opportunities in the company’s pipeline focus on RAS(ON) mutant-selective inhibitors, including RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C), in addition to RAS companion inhibitors RMC-4630 and RMC-5552. Revolution Medicines Investors & Media Contacts: investors@revmed.com; media@revmed.com

临床研究

2024-12-04

·GlobeNewswire-Health Care

Revolution Medicines Announces Pricing of Upsized $750.0 Million Public Offering of Common Stock and Pre-Funded Warrants

REDWOOD CITY, Calif., Dec. 03, 2024 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, today announced the pricing of 14,130,436 shares of its common stock at a public offering price of $46.00 per share, before underwriting discounts and commissions, and, in lieu of shares of common stock, to certain investors, pre-funded warrants to purchase 2,173,917 shares of common stock at a public offering price of $45.9999, which represents the per share public offering price for the common stock less the $0.0001 per share exercise price for each pre-funded warrant. All of the shares and pre-funded warrants in the offering are to be sold by Revolution Medicines. In addition, Revolution Medicines has granted the underwriters a 30-day option to purchase up to an additional 2,445,652 shares of common stock at the public offering price, less underwriting discounts and commissions. The gross proceeds from the offering are expected to be approximately $750.0 million before deducting underwriting discounts and commissions and other offering expenses, excluding any exercise of the underwriters’ option to purchase additional shares and excluding the exercise of any pre-funded warrants. The offering is expected to close on December 5, 2024, subject to customary closing conditions. J.P. Morgan, TD Cowen, Goldman Sachs & Co. LLC and Guggenheim Securities are acting as joint book-running managers for the offering. UBS Investment Bank is acting as lead manager. A shelf registration statement relating to these securities was filed with the U.S. Securities and Exchange Commission (SEC) on March 4, 2024, and automatically became effective upon filing. This offering is being made solely by means of a prospectus. A copy of the final prospectus supplement and the accompanying prospectus relating to this offering may be obtained for free by visiting EDGAR on the SEC’s website at www.sec.gov. Alternatively, a copy of the final prospectus supplement and the accompanying prospectus relating to this offering may be obtained by contacting: J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York 11717, by email at prospectus-eq_fi@jpmchase.com and postsalemanualrequests@broadridge.com; TD Securities (USA) LLC, 1 Vanderbilt Avenue, New York, New York 10017, by telephone at (855) 495-9846 or by email at TD.ECM_Prospectus@tdsecurities.com; Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, by telephone at (866) 471-2526 or by email at prospectus-ny@ny.email.gs.com; and Guggenheim Securities, LLC, Attention: Equity Syndicate Department, 330 Madison Avenue, 8th Floor, New York, New York 10017, by telephone at (212) 518-9544 or by email at GSEquityProspectusDelivery@guggenheimpartners.com. This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction. About Revolution Medicines, Inc. Revolution Medicines is a clinical-stage oncology company developing novel targeted therapies for RAS-addicted cancers. The company’s R&D pipeline comprises RAS(ON) inhibitors designed to suppress diverse oncogenic variants of RAS proteins. The company’s RAS(ON) inhibitors RMC-6236, a RAS(ON) multi-selective inhibitor, RMC-6291, a RAS(ON) G12C-selective inhibitor, and RMC-9805, a RAS(ON) G12D-selective inhibitor, are currently in clinical development. Additional development opportunities in the company’s pipeline focus on RAS(ON) mutant-selective inhibitors, including RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C), in addition to RAS companion inhibitors RMC-4630 and RMC-5552. Forward Looking Statements To the extent that statements contained in this press release are not descriptions of historical facts regarding Revolution Medicines, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including statements regarding the expected completion and timing of closing of the public offering. Such forward-looking statements involve risks and uncertainties, including, without limitation, risks and uncertainties related to market conditions and the satisfaction of closing conditions related to the public offering. Such forward-looking statements involve substantial risks and uncertainties that relate to future events, and the actual results could differ significantly from those expressed or implied by the forward-looking statements. Revolution Medicines undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties relating to Revolution Medicines’ business in general, see the prospectus supplement related to the public offering and Revolution Medicines’ current and future reports filed with the SEC, including Revolution Medicines’ Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, filed with the SEC on November 6, 2024.

2024-12-02

·GlobeNewswire-Health Care

Revolution Medicines Announces Commencement of Public Offering of Common Stock

REDWOOD CITY, Calif., Dec. 02, 2024 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, today announced that it has commenced an underwritten public offering to sell up to $600.0 million of shares of its common stock. All of the shares of common stock are being offered by Revolution Medicines. In addition, Revolution Medicines intends to grant the underwriters a 30-day option to purchase up to an additional $90.0 million of shares of common stock. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering. J.P. Morgan, TD Cowen, Goldman Sachs & Co. LLC and Guggenheim Securities are acting as joint book-running managers for the proposed offering. UBS Investment Bank is acting as lead manager. A shelf registration statement relating to these securities was filed with the U.S. Securities and Exchange Commission (SEC) on March 4, 2024, and automatically became effective upon filing. This offering is being made solely by means of a prospectus. A copy of the preliminary prospectus supplement and the accompanying prospectus relating to this offering may be obtained for free by visiting EDGAR on the SEC’s website at www.sec.gov. Alternatively, a copy of the preliminary prospectus supplement and the accompanying prospectus relating to this offering may be obtained by contacting: J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York 11717, by email at prospectus-eq_fi@jpmchase.com and postsalemanualrequests@broadridge.com; TD Securities (USA) LLC, 1 Vanderbilt Avenue, New York, New York 10017, by telephone at (855) 495-9846 or by email at TD.ECM_Prospectus@tdsecurities.com; Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, by telephone at (866) 471-2526 or by email at prospectus-ny@ny.email.gs.com; and Guggenheim Securities, LLC, Attention: Equity Syndicate Department, 330 Madison Avenue, 8th Floor, New York, New York 10017, by telephone at (212) 518-9544 or by email at GSEquityProspectusDelivery@guggenheimpartners.com. This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction. About Revolution Medicines, Inc. Revolution Medicines is a clinical-stage oncology company developing novel targeted therapies for RAS-addicted cancers. The company’s R&D pipeline comprises RAS(ON) inhibitors designed to suppress diverse oncogenic variants of RAS proteins. The company’s RAS(ON) inhibitors RMC-6236, a RAS(ON) multi-selective inhibitor, RMC-6291, a RAS(ON) G12C-selective inhibitor, and RMC-9805, a RAS(ON) G12D-selective inhibitor, are currently in clinical development. Additional development opportunities in the company’s pipeline focus on RAS(ON) mutant-selective inhibitors, including RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C), in addition to RAS companion inhibitors RMC-4630 and RMC-5552. Forward Looking Statements To the extent that statements contained in this press release are not descriptions of historical facts regarding Revolution Medicines, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including statements regarding completion, timing and size of the proposed public offering. Such forward-looking statements involve risks and uncertainties, including, without limitation, risks and uncertainties related to market conditions and the satisfaction of closing conditions related to the proposed public offering. Such forward-looking statements involve substantial risks and uncertainties that relate to future events, and the actual results could differ significantly from those expressed or implied by the forward-looking statements. Revolution Medicines undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties relating to Revolution Medicines’ business in general, see the preliminary prospectus supplement related to the proposed public offering and Revolution Medicines’ current and future reports filed with the SEC, including Revolution Medicines’ Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, filed with the SEC on November 6, 2024.

临床研究

100 项与 RMC-5552 相关的药物交易

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