Revolution Medicines Announces Publication Describing Molecular Basis of Tri-Complex Inhibitors Targeting Oncogenic RAS(ON) Proteins
17 Agosto 2023 - 5:05PM
Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage
oncology company developing targeted therapies for RAS-addicted
cancers, today announced the publication of a peer-reviewed
research paper in Science. This original research was led by
scientists at Revolution Medicines and conducted in collaboration
with researchers from Memorial Sloan Kettering Cancer Center.
The paper describes the Revolution Medicines
tri-complex inhibitor approach to developing novel small molecules
with high affinity and selectivity for the active state of mutant
RAS, or RAS(ON), proteins that are common causes of human cancer
and were previously considered undruggable. Specifically, it
describes the creation of innovative, natural product-inspired,
orally bioavailable small molecules, including the tool compound
RMC-4998 and the clinical candidate RMC-6291. These compounds are
shown to remodel the surface of the cellular chaperone cyclophilin
A (CYPA) to create a neomorphic interface with affinity for active
KRAS and achieve high selectivity for mutant KRASG12C via covalent,
irreversible binding to the cysteine residue in the active state of
this variant RAS protein that often drives formation of lung and
colorectal cancers. KRASG12C(ON) trapped in these tri-complexes is
sterically blocked from interacting with downstream effectors that
transmit cancer-causing signals. Both RMC-4998 and RMC-6291
inactivate oncogenic signaling in KRASG12C-dependent tumor cells
and drive deep and durable tumor regressions in human xenograft
models of these cancers.
“This research serves as preclinical validation
of our tri-complex RAS(ON) inhibitor platform and confirms our
ability to design potent, selective small molecules that target
KRAS mutations in their active or ON state,” said Steve Kelsey,
M.D., president, research and development at Revolution Medicines.
“These data provide the rationale for the RMC-6291 clinical
program, our first mutant-selective RAS(ON) inhibitor to enter
clinical development, which is currently underway. We look forward
to sharing a preliminary report of the clinical profile for
RMC-6291 at the AACR-NCI-EORTC International Conference on
Molecular Targets and Cancer Therapeutics (Triple Meeting) in
October 2023.”
The investigational agent RMC-6291, an oral,
selective, covalent inhibitor of KRASG12C(ON) designed to treat
patients with cancers driven by the KRASG12C variant, is the first
of the company’s mutant-selective RAS(ON) inhibitors to enter
clinical development and the first reported clinical-stage
inhibitor of KRASG12C that uses this highly differentiated
mechanism of action. Revolution Medicines is currently evaluating
RMC-6291 as monotherapy in a Phase 1/1b trial in patients with
advanced KRASG12C mutant solid tumors (NCT05462717).
The manuscript published In Science is entitled,
“Chemical remodeling of a cellular chaperone to target the active
state of mutant KRAS” and can be accessed at
https://www.science.org/doi/10.1126/science.adg9652.
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, and RAS Companion Inhibitors for use in combination
treatment strategies. The company’s RAS(ON) Inhibitors RMC-6236
(RASMULTI), RMC-6291(KRASG12C) and RMC-9805 (KRASG12D) are
currently in clinical development. Additional RAS(ON) Inhibitors in
the company’s pipeline include RMC-0708 (KRASQ61H) which is
currently in IND-enabling development, RMC-8839 (KRASG13C), and
additional compounds targeting other RAS variants. RAS Companion
Inhibitors in clinical development include RMC-4630 (SHP2) and
RMC-5552 (mTORC1/4EBP1).
Forward Looking Statements
This press release contains forward-looking
statements within the meaning of the U.S. Private Securities
Litigation Reform Act of 1995. Any statements in this press release
that are not historical facts may be considered "forward-looking
statements," including without limitation statements regarding the
tolerability and potential efficacy of Revolution Medicines’
clinical candidates, including RMC-6291 and its clinical profile;
the outcome of the company’s clinical trials, including the Phase
1/1b study of RMC-6291; and validation of the company’s platform
and its ability to design small molecules. Forward-looking
statements are typically, but not always, identified by the use of
words such as "may," "will," "would," "believe," "intend," "plan,"
"anticipate," "estimate," "expect," and other similar terminology
indicating future results. Such forward-looking statements are
subject to substantial risks and uncertainties that could cause our
development programs, future results, performance or achievements
to differ materially from those anticipated in the forward-looking
statements. Such risks and uncertainties include without limitation
risks and uncertainties inherent in the drug development process,
including the company’s programs’ early stage of development, the
process of designing and conducting preclinical and clinical
trials, the regulatory approval processes, the timing of regulatory
filings, the challenges associated with manufacturing drug
products, the company’s ability to successfully establish, protect
and defend its intellectual property, other matters that could
affect the sufficiency of the company’s capital resources to fund
operations, reliance on third parties for manufacturing and
development efforts, changes in the competitive landscape and the
effects on our business of the worldwide COVID-19 pandemic. For a
further description of the risks and uncertainties that could cause
actual results to differ from those anticipated in these
forward-looking statements, as well as risks relating to the
business of Revolution Medicines in general, see Revolution
Medicines’ Quarterly Report on Form 10-Q filed with the Securities
and Exchange Commission on August 8, 2023, and its future periodic
reports to be filed with the Securities and Exchange Commission.
Except as required by law, Revolution Medicines undertakes no
obligation to update any forward-looking statements to reflect new
information, events, or circumstances, or to reflect the occurrence
of unanticipated events.
Investors & Media Contact:
Erin Graves
650-779-0136
egraves@revmed.com
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