Author: Zhou, Guizhen ; Zheng, Mingyue ; Li, Yupeng ; Huo, Ruifeng ; Gu, Yuejiao ; Zhou, Chuan ; Ge, Zhiming ; Fan, Zisheng ; Xu, Tianfeng ; He, Wei ; Wang, Dan ; Tao, Zhaofan ; Gao, Mingshan ; Zhang, Sulin ; Cui, Rongrong

KRAS^G12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRAS^G12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRAS^G12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRAS^G12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRAS^G12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRAS^G12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition.

01 Dec 2023·Journal of proteome research

Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRAS^G12D Inhibitor MRTX1133

Article

Author: Orsburn, Benjamin C

Mutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has shown promise in inhibiting the activity of KRAS^G12D mutant proteins, which is one of the main drivers of pancreatic cancer. To better understand the mechanism of action of this compound, I performed both proteomics and metabolomics on four KRAS^G12D mutant pancreatic cancer cell lines. To obtain increased granularity in the proteomic observations, single-cell proteomics was successfully performed on two of these lines. Following quality filtering, a total of 1498 single cells were analyzed. From these cells, 3140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.

23 Nov 2023·Journal of medicinal chemistryQ1 · MEDICINE

Design, Synthesis, and Pharmacological Evaluation of Multisubstituted Pyrido[4,3-d]pyrimidine Analogues Bearing Deuterated Methylene Linkers as Potent KRAS^G12D Inhibitors

Q1 · MEDICINE

Article

Author: Liu, Xiaogu ; Feng, Juanjuan ; Zhang, Ao ; Xiao, Xuanzheng ; Xia, Xinting ; Zhang, Jian ; Ding, Chunyong ; Ma, Jing ; Pang, Xiufeng

The breakthrough in drug development of KRAS^G12C inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS^G12D variant. Based on the structural analysis of MRTX1133 in complex with KRAS^G12D, a comprehensive structure-activity study was conducted, which led to the discovery of several compounds (22, 28, and 31) that showed higher potency in suppressing the clonogenic growth of KRAS^G12D-dependent cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRAS^G12D with IC₅₀ values between 0.48 and 1.21 nM. These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high in vitro and in vivo potency of these new inhibitors call for further profiling.

News (Medical) associated with MRTX-1133

05 Apr 2024

·www.biospace.com

Novocure Announces 20 Presentations On Tumor Treating Fields, Highlighting Preclinical Effects in Pancreatic Cancer and Immune Effects, at American Association for Cancer Research (AACR) Annual Meeting 2024

ROOT, Switzerland--(BUSINESS WIRE)-- Novocure (NASDAQ: NVCR) today announced 20 presentations on Tumor Treating Fields (TTFields) therapy will be delivered at the American Association for Cancer Research (AACR) Annual Meeting 2024, to be held April 5 to 10 in San Diego. The presentations, describing preclinical investigations, include new insights on how TTFields therapy can potentially enhance the immune system’s ability to combat cancer cells and on TTFields therapy’s effects and mechanisms in pancreatic cancer. “The research we and our collaborators are presenting at the AACR Annual Meeting underscores the potential of Tumor Treating Fields therapy in treating various solid tumor types,” said Moshe Giladi, Ph.D., Novocure’s Chief Science Officer. “We continually explore the science of TTFields therapy to improve our product and make a difference in the lives of patients with cancer, and we are eager to discuss some of our latest insights with leading cancer investigators.” Highlights include: A preclinical study in a murine model of pancreatic cancer showing that TTFields applied concurrently with standard chemotherapy led to significantly enhanced therapeutic effects. When used alongside gemcitabine and nab-paclitaxel (Gem/NabP), TTFields significantly reduced tumor growth compared to the control group, and a complete regression of tumors was observed in a number of animals. This is a treatment regimen similar to the PANOVA-3 clinical trial examining the efficacy of TTFields in patients with locally advanced pancreatic cancer. A preclinical study demonstrating a novel immunomodulatory role for TTFields by promoting in vitro pro-inflammatory polarization of macrophages. Macrophages exposed to TTFields showed an increase in markers and chemicals that indicate a shift towards a pro-inflammatory, tumor-fighting mode. The study suggests TTFields can potentially modulate macrophages to better attack cancer cells by pushing them toward a state more hostile to tumors. An in vitro study suggesting concomitant application of TTFields and PARP inhibitors in BRCA wild type pancreatic cancer cells leads to improvement over monotherapy. Applied individually, both PARP inhibitors and TTFields killed cancer cells, stopped them from multiplying, and triggered apoptosis. These effects were amplified when TTFields and PARP inhibitors were applied together. These findings contribute to existing data suggesting that TTFields induce a state of BRCAness in cancer cells. Presentations from Novocure-sponsored and partner programs include: Tumor Treating Fields (TTFields) targeted self assembling nanoparticles for pancreatic cancer treatment: In vitro and in vivo assessment. Presenter: P.P. Desai. 1:30 p.m. PDT on Sunday, April 7. Tumor Treating Fields induce the integrated stress response, alter the transcriptional signatures of cellular metabolism, and modulate immune-related cytokines dependent and independent of p53. Presenter: P.R. Srinivasan. 1:30 p.m. PDT on Sunday, April 7. Tumor Treating Fields (TTFields) disrupt cancer cell invasion by impacting cell-ECM traction forces. Presenter: S.M. Short. 9 a.m. PDT on Monday, April 8. N-cadherin-mediated activation of PI3K/Akt pathway following application of Tumor Treating Fields (TTFields). Presenter: T. Voloshin. 9 a.m. PDT on Monday, April 8. Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure. Presenter: M. Mazzanti. 9 a.m. PDT on Monday, April 8. Co-treatment with KRAS G12D inhibitor MRTX1133 plus TTFields against human pancreatic and Colorectal cancer cell lines results in synergistic up-regulation of cleaved PARP in KRAS G12D & unexpectedly in KRAS G12V as well. Presenter: V. Tajiknia. 9 a.m. PDT on Monday, April 8. Tumor Treating Fields (TTFields) for spinal metastasis: Clinical trial concept for use of conductive implants as waveguides to enhance TTFields strength. Presenter: C.E. Tatsui. 9 a.m. PDT on Monday, April 8. Tumor Treating Fields (TTFields) increase cancer cell membrane permeability and improve sensitivity to doxorubicin in vitro and in vivo. Presenter: T. Voloshin. 9 a.m. PDT on Tuesday, April 9. Development of paclitaxel-loaded nanoparticles with high charge density. Presenter: K.Y. Bang. 1:30 p.m. PDT on Tuesday, April 9. Tumor Treating Fields alter PDGFR-β localization in immortalized human pericytes in an in vitro model of the blood-brain barrier. Presenter: C. Hagemann. 1:30 p.m. PDT on Tuesday, April 9. Designing arrays for delivering Tumor Treating Fields (TTFields) to the mouse head. Presenter: I Tzchori. 1:30 p.m. PDT on Tuesday, April 9. Tumor Treating Fields (TTFields) induce an anti-tumor immune response in a pancreatic cancer mouse model. Presenter: T. Voloshin. 9 a.m. PDT on Wednesday, April 10. Macrophage pro-inflammatory phenotype skewing by the application of Tumor Treating Fields (TTFields). Presenter: T. Voloshin. 9 a.m. PDT on Wednesday, April 10. Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma. Presenter: Q. Mei. 9 a.m. PDT on Wednesday, April 10. Treatment of pancreatic cancer cells with Tumor Treating Fields (TTFields) and PARP inhibitors. Presenter: E. Dor-On. 9 a.m. PDT on Wednesday, April 10. Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer. Presenter: E. Dor-On. 9 a.m. PDT on Wednesday, April 10. Preclinical investigations of concomitant Tumor Treating Fields (TTFields) with cisplatin for treatment of cervical cancer. Presenter: I. Tzschori. 9 a.m. PDT on Wednesday, April 10. Tumor Treating Fields (TTFields) can induce immunogenic cell death in GBM resulting in enhanced immune modulation. Presenter: R.T. Nitta. 9 a.m. PDT on Wednesday, April 10. Tumor Treating Fields (TTFields) show efficacy in Triple-Negative breast cancer (TNBC) cells alone and in combination with PARP inhibitor Talazoparib. Presenter: M. Ghandali. 9 a.m. PDT on Wednesday, April 10. TTFields and imipridone ONC206 co-treatment inhibits p-AKT and spheroid growth and upregulates caspase-10 in human GBM cell lines. Presenter: V. Tajiknia. 9 a.m. PDT on Wednesday, April 10. ABOUT TUMOR TREATING FIELDS THERAPY Tumor Treating Fields (TTFields) are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. TTFields do not significantly affect healthy cells because they have different properties (including division rate, morphology, and electrical properties) than cancer cells. The multiple, distinct mechanisms of TTFields therapy work together to selectively target and kill cancer cells. Due to its multimechanistic actions, TTFields therapy can be added to cancer treatment modalities in approved indications and demonstrates enhanced effects across solid tumor types when used with chemotherapy, radiotherapy, immune checkpoint inhibition, or PARP inhibition in preclinical models. TTFields therapy provides clinical versatility that has the potential to help address treatment challenges across a range of solid tumors. To learn more about Tumor Treating Fields therapy and its multifaceted effect on cancer cells, visit tumortreatingfields.com. ABOUT NOVOCURE Novocure is a global oncology company working to extend survival in some of the most aggressive forms of cancer through the development and commercialization of its innovative therapy, Tumor Treating Fields. Novocure’s commercialized products are approved in certain countries for the treatment of adult patients with glioblastoma, malignant pleural mesothelioma and pleural mesothelioma. Novocure has ongoing or completed clinical studies investigating Tumor Treating Fields in brain metastases, gastric cancer, glioblastoma, liver cancer, non-small cell lung cancer, pancreatic cancer and ovarian cancer. Headquartered in Root, Switzerland and with a growing global footprint, Novocure has regional operating centers in Portsmouth, New Hampshire and Tokyo, as well as a research center in Haifa, Israel. For additional information about the company, please visit Novocure.com and follow @Novocure on LinkedIn and Twitter. FORWARD-LOOKING STATEMENTS In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Novocure’s current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs, clinical study progress, development of potential products, interpretation of clinical results, prospects for regulatory approval, manufacturing development and capabilities, market prospects for its products, coverage, collections from third-party payers and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as “could” “anticipate,” “estimate,” “expect,” “project,” “intend,” “plan,” “believe” or other words and terms of similar meaning. Novocure’s performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, environmental, regulatory and political conditions and other more specific risks and uncertainties facing Novocure such as those set forth in its Annual Report on Form 10-K filed on February 22, 2024, and subsequent filings with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Novocure does not intend to update publicly any forward-looking statement, except as required by law. Any forward-looking statements herein speak only as of the date hereof. The Private Securities Litigation Reform Act of 1995 permits this discussion. View source version on businesswire.com: Contacts INVESTORS & MEDIA: Ingrid Goldberg investorinfo@novocure.com media@novocure.com 610-723-7427 Source: Novocure View this news release online at:

Immunotherapy

10 Jan 2024

·www.prnewswire.com

European Commission Approves KRAZATI (adagrasib) as a Targeted Treatment Option for Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation

SAN DIEGO and ZUG, Switzerland, Jan. 10, 2024 /PRNewswire/ -- Mirati Therapeutics, Inc.® (NASDAQ: MRTX), a commercial stage biotechnology company, today announced that the European Commission (EC) granted conditional marketing authorization for KRAZATI® (adagrasib) as a targeted treatment option for adult patients with KRASG12C -mutated advanced non-small cell lung cancer (NSCLC) and disease progression after at least one prior systemic therapy. KRAZATI has demonstrated a positive benefit-risk profile based on the Phase 2 registration-enabling cohort of the KRYSTAL-1 study, evaluating KRAZATI 600 mg administered orally twice daily in 116 patients with KRASG12C-mutated advanced NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor. The primary efficacy endpoints were confirmed ORR and DOR as evaluated by blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST v1.1). "KRAZATI offers an efficacious and tolerable therapeutic option for patients living with advanced KRASG12C -mutated NSCLC and this approval expands the potential treatment options available," Martin Reck, MD, PhD, Lung Clinic Grosshansdorf, Germany. "With it's differentiated profile, KRAZATI offers an impactful treatment option for patients living with lung cancer. This approval will assist physicians in tailoring treatment approaches for patients." Conditional marketing authorization for KRAZATI is valid in all 27 EU member states plus Iceland, Norway and Liechtenstein. This authorization follows the positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) in November 2023. "This is a meaningful day for patients living with this difficult-to-treat cancer in the European Union as we can now offer a differentiated and potentially best-in-class therapeutic option to this underserved population," Charles Baum, M.D., PhD, founder, president and chief executive officer, Mirati Therapeutics, Inc., "Mirati is resolute in our commitment to improve upon treatment options for these patients and looks forward to continued partnership with EU members states to create broad access for all qualified patients." Mirati thanks the patients, physicians, investigators and site coordinators who participated in the clinical trials that led to this important approval. Important Safety Information The Summary of Product Characteristics (SmPC) for KRAZATI (adagrasib) will be available from the European Medicines Agency at the Union Register of medicinal products. About KRAZATI (adagrasib) Mirati has risen to meet one of the most challenging mutations in cancer research by developing KRAZATI, a highly selective and potent oral small-molecule inhibitor of KRASG12C. Intentionally designed to meet the challenge of KRASG12C, adagrasib is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24−48 hours.1 Adagrasib has shown clinically to be a CNS penetrant, which may be important given that CNS metastases frequently occur in NSCLC and lead to poor prognosis.2-34 The FDA provided KRAZATI Accelerated Approval (Subpart H), allowing for the approval of drugs that treat serious conditions, and that fill an unmet medical need based on surrogate endpoints. Adagrasib continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer. For more information, visit Mirati.com/science. About the KRYSTAL-1 Study KRYSTAL-1 is an open-label Phase 1/2 multiple-expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anti-cancer therapies in patients with advanced solid tumors harboring the KRASG12C mutation. About KRASG12C in NSCLC Lung cancer is one of the most common cancers worldwide, accounting for 2.21 million new cases and 1.8 million deaths worldwide in 2020.5 Lung cancer consists of NSCLC in approximately 85% of cases and small cell lung cancer (SCLC) in approximately 15% of cases.6 KRASG12C is the most common KRAS mutation in NSCLC, present in approximately 14% of patients with lung adenocarcinoma, and is a biomarker mutation of poor prognosis.1,3 About Mirati Therapeutics, Inc. Mirati Therapeutics, Inc. is a commercial stage biotechnology company whose mission is to discover, design and deliver breakthrough therapies to transform the lives of patients with cancer and their loved ones. The company is relentlessly focused on bringing forward therapies that address areas of high unmet need, including lung cancer, and advancing a pipeline of novel therapeutics targeting the genetic and immunological drivers of cancer. Unified for patients, Mirati's vision is to unlock the science behind the promise of a life beyond cancer. For more information about Mirati, visit us at Mirati.com or follow us on Twitter, LinkedIn and Facebook. Forward Looking Statements This press release includes forward-looking statements regarding Mirati's business, financial guidance and the therapeutic and commercial potential of KRAZATI® (adagrasib), MRTX1719 (MTA-cooperative PRMT5 inhibitor), MRTX0902 (SOS1 inhibitor), and MRTX1133 (selective KRASG12D inhibitor), Mirati's technologies and Mirati's other products in development. Any statement describing Mirati's goals, expectations, intentions or beliefs, financial or other projections, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including those related to the impact COVID-19 could have on our business, and including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Mirati's forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Mirati's forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Mirati. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Mirati's programs are described in additional detail in Mirati's annual report on Form 10-K, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission and available at the SEC's Internet site (). These forward-looking statements are made as of the date of this press release, and Mirati assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Mirati Contacts Investor Relations: [email protected] Media Relations: [email protected] References 1 Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2020;10(1):54-71. 2 Sabari JK, Velcheti V, Shimizu K, et al. Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2022;28(15):3318-3328. 3 Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017;19(11):1511-1521. 4 Ali A, Goffin JR, Arnold A, Ellis PM. Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr Oncol. 2013;20(4):e300-6. 5 Lung cancer statistics. WCRF International. . Published April 14, 2022. 6 Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-94. SOURCE Mirati Therapeutics, Inc.

Clinical ResultDrug ApprovalPhase 2Accelerated Approval

10 Nov 2023

·www.biospace.com

Mirati Therapeutics Receives Positive Opinion from CHMP for KRAZATI (adagrasib) as a Targeted Treatment Option for Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation Following a Re-Examination Procedure

SAN DIEGO, Calif. and ZUG, Switzerland, Nov. 10, 2023 /PRNewswire/ -- Mirati Therapeutics, Inc.® (NASDAQ: MRTX), a commercial stage biotechnology company, today announced that following a re-examination procedure, the Company has received a positive opinion from the European Medicine Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) on KRAZATI® (adagrasib) as a targeted treatment option for adult patients with KRASG12C -mutated advanced non-small cell lung cancer (NSCLC) and disease progression after at least one prior systemic therapy. "Today's positive opinion from the CHMP for KRAZATI marks an important step on the path to providing access to a potentially best-in-class therapeutic option to patients living with this difficult-to-treat disease," Alan Sandler, M.D., chief medical officer, Mirati Therapeutics, Inc. "We look forward to approval from the European Commission and the opportunity to positively impact the lives of eligible patients living in the European Union." "This is an important day for the oncology community as we step closer to a new therapeutic option being available to patients living with KRASG12C mutated NSCLC in the European Union," said Martin Reck, MD, PhD, Lung Clinic Grosshansdorf, Germany. "Every patient has a slightly different case so as more options become available physicians will better be able to tailor their treatment for each patient." About KRAZATI® (adagrasib) Mirati has risen to meet one of the most challenging mutations in cancer research by developing KRAZATI, a highly selective and potent oral small-molecule inhibitor of KRASG12C. Intentionally designed to meet the challenge of KRASG12C, adagrasib is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24−48 hours.1 Adagrasib has shown clinically to be a CNS penetrant, which may be important given that CNS metastases frequently occur in NSCLC and lead to poor prognosis.2,3,4 The FDA provided KRAZATI Accelerated Approval (Subpart H), allowing for the approval of drugs that treat serious conditions, and that fill an unmet medical need based on surrogate endpoints. KRAZATI was also granted a conditional marketing authorization by the United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) on November 3, 2023. Adagrasib continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer. For more information, visit Mirati.com/science. About the KRYSTAL-1 Study KRYSTAL-1 is an open-label Phase 1/2 multiple-expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anti-cancer therapies in patients with advanced solid tumors harboring the KRASG12C mutation. About KRASG12C in NSCLC Lung cancer is one of the most common cancers worldwide, accounting for 2.21 million new cases and 1.8 million deaths worldwide in 2020.5 Lung cancer consists of NSCLC in approximately 85% of cases and small cell lung cancer (SCLC) in approximately 15% of cases.6 KRASG12C is the most common KRAS mutation in NSCLC, present in approximately 14% of patients with lung adenocarcinoma, and is a biomarker mutation of poor prognosis.1,3 About Mirati Therapeutics, Inc. Mirati Therapeutics, Inc. is a commercial stage biotechnology company whose mission is to discover, design and deliver breakthrough therapies to transform the lives of patients with cancer and their loved ones. The company is relentlessly focused on bringing forward therapies that address areas of high unmet need, including lung cancer, and advancing a pipeline of novel therapeutics targeting the genetic and immunological drivers of cancer. Unified for patients, Mirati's vision is to unlock the science behind the promise of a life beyond cancer. For more information about Mirati, visit us at Mirati.com or follow us on Twitter, LinkedIn, and Facebook. Forward Looking Statements This press release includes forward-looking statements regarding Mirati Therapeutic, Inc.'s ("Mirati") business, the therapeutic and commercial potential of KRAZATI® (adagrasib), MRTX1719 (MTA-cooperative PRMT5 inhibitor), MRTX0902 (SOS1 inhibitor), and MRTX1133 (selective KRASG12D inhibitor), and Mirati's technologies and other products in development. Any statement describing Mirati's goals, expectations, intentions or beliefs, financial or other projections, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, the endeavor of building a business around such medicines, and the proposed acquisition of Mirati by Bristol-Myers Squibb Company. Mirati's forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Mirati's forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Mirati. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Mirati's programs are described in additional detail in Mirati's annual report on Form 10-K, and most recent Form 10-Q, which are on the Securities and Exchange Commission (the "SEC") and available at the SEC's website ( ). These forward-looking statements are made as of the date of this press release, and Mirati assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Mirati Contacts Investor Relations: ir@mirati.com Media Relations: media@mirati.com References 1 Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2020;10(1):54-71. 2 Sabari JK, Velcheti V, Shimizu K, et al. Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2022;28(15):3318-3328. 3 Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017;19(11):1511-1521. 4 Ali A, Goffin JR, Arnold A, Ellis PM. Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr Oncol. 2013;20(4):e300-6. 5 Lung cancer statistics. WCRF International. . Published April 14, 2022. 6 Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-94. Company Codes: NASDAQ-SMALL:MRTX

Drug ApprovalAccelerated Approval

100 Deals associated with MRTX-1133

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	US	Mirati Therapeutics, Inc.	20 Mar 2023
Colorectal Cancer	Phase 2	US	Mirati Therapeutics, Inc.	20 Mar 2023
Non-Small Cell Lung Cancer	Phase 2	US	Mirati Therapeutics, Inc.	20 Mar 2023
Pancreatic adenocarcinoma	Phase 2	US	Mirati Therapeutics, Inc.	20 Mar 2023

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


B032 (AACR_Targeting RAS2023)	Not Applicable	Pancreatic Cancer	-	MRTX1133	lqtpyxlkof(tnndzltzbq) = zkhagzmwds jlwupwqqwz (axxgbgtbwc )	Positive	01 May 2023

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