BANF1

引言虽然癌基因可以被小分子抑制，但肿瘤抑制蛋白的丢失更为常见，并且存在问题，因为肿瘤抑制蛋白不再存在靶向。值得注意的例子包括SMARCB1 突变癌症，这是由SWI/SNF（也称为 BAF）染色质重塑复合物亚基失活驱动的高度致命的恶性肿瘤。2024年3月27日，圣裘德儿童研究医院Charles W. M. Roberts及哈佛医学院Eric S. Fischer共同通讯在Nature 在线发表题为“Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF”的研究论文，该研究表明靶向DCAF5通过稳定SWI/SNF抑制SMARCB1突变癌症。为了深入了解SMARCB1突变的后果并识别漏洞，研究人员将14个SMARCB1突变细胞系用于近全基因组CRISPR筛选，作为癌症依赖图谱项目的一部分。该研究报道了很少被研究的基因 DDB1-CUL4相关因子5 (DCAF5)是SMARCB1突变癌症存活所必需的。该研究发现DCAF5对SWI/SNF复合物具有质量控制功能，并在没有SMARCB1的情况下促进不完全组装的SWI/SNF复合物的降解。在DCAF5耗尽后，SMARCB1缺陷的SWI/SNF复合物重新积累，结合靶位点，并将SWI/SNF介导的基因表达恢复到足以逆转癌症状态的水平，包括在体内。因此，癌症的发生不是由于SMARCB1功能本身的丧失，而是由于DCAF5介导的SWI/SNF复合物的降解。这些数据表明，针对泛素介导的质量控制因子的治疗可能有效地逆转一些由肿瘤抑制复合物破坏驱动的恶性状态。SWI/SNF染色质重塑复合物水解ATP，动员核小体在增强子和启动子处调节DNA可及性和基因表达。核心亚基SMARCB1在分裂过程中对增强子功能和细胞记忆的控制至关重要，最近的结构研究表明，它作为一个锚点结合到核小体酸性补丁上，在那里它为SWI/SNF重塑活性提供了有利条件。编码SWI/SNF亚基的基因在近25%的癌症患者中发生突变。SWI/SNF亚基SMARCB1失活发生在几种侵袭性癌症类型中，包括横纹肌样肿瘤(RTs)和肉瘤。SMARCB1是一种真正的肿瘤抑制因子，因为种系突变易导致癌症，在小鼠中缺失SMARCB1会导致所有小鼠的快速发病癌症。RTs具有简单的二倍体基因组，SMARCB1的缺失通常是唯一确定的驱动突变。由于SMARCB1肿瘤抑制蛋白缺失，唯一的驱动突变不能直接靶向治疗。因此，识别SMARCB1突变细胞特有的遗传脆弱性有可能深入了解SMARCB1缺失促进癌症的机制，并为治疗方法提供信息。癌症依赖图谱项目(DepMap)是一个大规模的合作项目，利用数百种癌细胞系系统地识别遗传依赖性、小分子敏感性和识别预测它们的生物标志物。为了寻找SMARCB1突变癌症的遗传脆弱性，研究人员向DepMap提供了14个SMARCB1突变的RT系，用于近全基因组CRISPR-Cas9功能缺失筛查。RTs中DCAF5丢失的机制模型（Credit: Nature）该研究确定了一种作用不同的合成致死关系。而不是产生毒性，靶向灭活质量控制因子实质上恢复多亚基蛋白复合物的功能，否则在失去肿瘤抑制亚基后降解。之前已经证明，SMARCB1缺失通过损害高增殖祖细胞中增强子的激活来驱动癌症，从而阻断分化并使其持续增殖。从机制上讲，DCAF5的失活可恢复大量SWI/SNF功能，恢复分化并逆转癌症表型。研究发现，在SMARCB1缺失的情况下，DCAF5通过促进SWI/SNF亚基的降解，对SWI/SNF复合物具有质量控制功能。之前证明，SMARCB1的缺失比SMARCA4或ARID1A的缺失导致SWI/SNF复合物更大的不稳定，这可能解释了与其他SWI/SNF突变型癌症相比，SMARCB1突变型癌症对DCAF5的优先依赖性。总的来说，该研究揭示了一种机制，该机制是多蛋白复合物质量控制的基础，并构成了肿瘤抑制基因突变失活驱动的癌症中可靶向的合成致命易感性。原文链接https://www.nature.com/articles/s41586-024-07250-1责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

Company management will review key pipeline programs, including an update on FHD-286 for AML, new preclinical data for the BRM selective inhibitor FHD-909 and for its selective CBP and EP300 degrader programs Conference call and webcast on April 9th at 5 p.m. ET / 2 p.m. PT CAMBRIDGE, Mass., March 26, 2024 (GLOBE NEWSWIRE) -- March 26, 2024 -- Foghorn® Therapeutics Inc. (Nasdaq: FHTX), a clinical-stage biotechnology company pioneering a new class of medicines that treat serious diseases by correcting abnormal gene expression, today announced plans to host a conference call and webcast on April 9th at 5 p.m. ET / 2 p.m. PT. Foghorn management will review key programs in its pipeline, including FHD-286 for acute myelogenous leukemia (AML), and new preclinical data being presented at the 2024 American Association for Cancer Research (AACR) Annual Meeting for potential first-in-class medicines including FHD-909, a BRM (SMARCA2) selective inhibitor, and for the selective CBP and selective EP300 degrader programs. Conference Call Details Tuesday, April 9, at 5 p.m. ET / 2 p.m. PT Toll Free: 1-877-704-4453 International: 1-201-389-0920 Conference ID: 13745314 Webcast: Foghorn Events and Presentations About Foghorn Therapeutics Foghorn® Therapeutics is discovering and developing a novel class of medicines targeting genetically determined dependencies within the chromatin regulatory system. Through its proprietary scalable Gene Traffic Control® platform, Foghorn is systematically studying, identifying and validating potential drug targets within the chromatin regulatory system. The Company is developing multiple product candidates in oncology. Visit our website at for more information on the Company, and follow us on X (formerly Twitter) and LinkedIn. About FHD-286 FHD-286 is a highly potent, selective, allosteric, and orally available small-molecule, enzymatic inhibitor of BRG1 (SMARCA4) and BRM (SMARCA2), two highly similar proteins that are the ATPases, or the catalytic engines, of the BAF complex, one of the key regulators within the chromatin regulatory system. In preclinical studies, FHD-286 has shown anti-tumor activity across a broad range of malignancies including both hematologic and solid tumors. About AML Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow and the most common type of acute leukemia in adults. AML is a diverse disease associated with multiple genetic mutations. It is diagnosed in about 20,000 people every year in the United States. About FHD-909 FHD-909 (a.k.a. LY4050784) is a highly potent, allosteric and orally available small molecule that selectively inhibits the ATPase activity of BRM (SMARCA2) over its closely related paralog BRG1 (SMARCA4), two proteins that are the catalytic engines across all forms of the BAF complex, one of the key regulators of the chromatin regulatory system. In preclinical studies, tumors with mutations in BRG1 rely on BRM for BAF function. FHD-909 has shown significant anti-tumor activity across multiple BRG1-mutant lung tumor models. Forward-Looking Statements This press release contains “forward-looking statements.” Forward-looking statements include statements regarding the Company’s clinical trials, product candidates and research efforts, including statements relating to FHD-286, FHD-909 and its selective CBP and EP 300 degrader programs, and other statements identified by words such as “could,” “may,” “might,” “will,” “likely,” “anticipates,” “intends,” “plans,” “seeks,” “believes,” “estimates,” “expects,” “continues,” “projects” and similar references to future periods. Forward-looking statements are based on our current expectations and assumptions regarding capital market conditions, our business, the economy and other future conditions. Because forward-looking statements relate to the future, by their nature, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. As a result, actual results may differ materially from those contemplated by the forward-looking statements. Important factors that could cause actual results to differ materially from those in the forward-looking statements include regional, national or global political, economic, business, competitive, market and regulatory conditions, including risks relating to our clinical trials and other factors set forth under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the Securities and Exchange Commission. Any forward-looking statement made in this press release speaks only as of the date on which it is made. Contacts: Greg Dearborn, Foghorn Therapeutics Inc. (Investors) gdearborn@foghorntx.com Karin Hellsvik, Foghorn Therapeutics Inc. (Investors & Media) khellsvik@foghorntx.com Adam Silverstein, ScientPR (Media) adam@scientpr.com Peter Kelleher, LifeSci Advisors (Investors) pkelleher@lifesciadvisors.com

• Dose escalation in FHD-286 combination study in AML continues to progress; clinical data anticipated in the second half of 2024 • FHD-909, a first-in-class BRM selective inhibitor, selected for clinical development by partner Lilly; preclinical data to be presented at AACR with IND planned for the second quarter, primary target patient population in non-small cell lung cancer • Selective CBP and EP300 degrader preclinical data to be presented at AACR; IND-enabling studies for CBP degrader program planned to begin by end of 2024 • Foghorn anticipates at least six new INDs targeting significant oncology patient populations over the next four years, reflecting the continued productivity of its precision medicine platform • Cash, cash equivalents, and marketable securities of $234.1 million, as of December 31, 2023, provide cash runway into the first half of 2026 CAMBRIDGE, Mass., March 07, 2024 (GLOBE NEWSWIRE) -- Foghorn® Therapeutics Inc. (Nasdaq: FHTX), a clinical-stage biotechnology company pioneering a new class of medicines that treat serious diseases by correcting abnormal gene expression, today provided a financial update and corporate outlook in conjunction with the Company’s 10-K filing for the year ending December 31, 2023. With an initial focus in oncology, Foghorn’s Gene Traffic Control® Platform and resulting broad pipeline have the potential to transform the lives of people with a wide spectrum of diseases. “The research and clinical advances we made in 2023 set the stage for Foghorn to deliver significant value with the potential for several differentiated, high-impact medicines in 2024 and beyond,” said Adrian Gottschalk, President and Chief Executive Officer of Foghorn. “In 2023 we initiated a combination study with FHD-286 in AML, with data anticipated in the second half of 2024. Based on the mutation-agnostic differentiation effect observed in our single-agent escalation study, we believe FHD-286 has the potential to be a first-in-class broad-based differentiation therapeutic in AML. We are also making progress with our selective BRM program with FHD-909, a first-in-class BRM selective inhibitor, selected for clinical development by partner Lilly. The IND is planned for the second quarter of 2024, with an initial focus in non-small cell lung cancer. Finally, we are excited by the preclinical efficacy and safety data for our CBP and EP300 selective degrader programs and target IND-enabling studies for CBP by the end of the year. Our cash position remains strong with runway into the first half of 2026.” Key Recent Updates and Upcoming Milestones FHD-286. FHD-286 is a potent, selective inhibitor of the BRG1 and BRM subunits of the BAF chromatin remodeling complex where dependency on BRG1/BRM is well-established preclinically with multiple tumor types, including acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS), non-small cell lung cancer (NSCLC) and prostate cancer. AML Update. Foghorn commenced a Phase 1 study of FHD-286 in combination with decitabine or low-dose cytarabine (LDAC) in relapsed and/or refractory AML patients, with the first patient dosed during the third quarter of 2023. Dose escalation is ongoing, and the first clinical data are expected in the second half of 2024.TKI Resistance. Recently published data, along with Foghorn’s work, suggest that FHD-286 may play an important role in overcoming resistance in EGFR/KRAS tumors. The Company is conducting preclinical work to further explore the opportunity and expects data in the second quarter of 2024. Differentiated Pipeline Advancement. Foghorn continues to expand its platform and pipeline. The Company anticipates the potential for six new investigational new drug (IND) applications in the next four years. The Company continues to progress programs for multiple targets that include chromatin remodeling complexes, transcription factors, helicases, and other chromatin-related factors. These targets include selective BRM and wholly owned programs including CBP, EP300, and ARID1B, as well as other undisclosed targets, which combined could address more than 20 tumor types impacting more than 500,000 new patients annually. Selective CBP and Selective EP300 programs. Foghorn is presenting new preclinical data for its CBP and EP300 selective degrader programs at the 2024 AACR Annual Meeting, April 5-10, 2024. CBP selective degraders have shown significant tumor growth inhibition in a colorectal cancer in vivo model. Antiproliferative effects were also observed for numerous cancer cell lines, including colorectal, gastric and bladder cancers.EP300 selective degraders have shown potent cellular antiproliferation and in vivo tumor growth inhibition in an AR+ enzalutamide prostate in vivo model.At preclinical efficacious doses, neither the CBP nor the EP300 selective degraders cause thrombocytopenia, a commonly observed safety liability for dual CBP/EP300 inhibitors. Lilly Collaboration. Foghorn is engaged in a strategic collaboration with Lilly and continues to advance the BRM selective inhibitor and degrader programs along with other undisclosed programs. In the first quarter of 2024, Lilly selected FHD-909, a first-in-class oral BRM selective inhibitor, for clinical development. Lilly plans to file an IND for FHD-909 in the second quarter of 2024. The primary target patient population is BRG1-mutated NSCLC.Selective BRM inhibition has been a sought-after objective in cancer research for many years. A variety of tumor types, including NSCLC, are known to have mutations in BRG1, which we believe make them dependent on BRM activity for their survival. Selective blocking of BRM activity is considered a promising strategy for causing tumor cell death while sparing healthy cells.Preclinical data will be presented in 2024, including at AACR with a poster presentation on April 8. In December 2021, Foghorn announced a strategic collaboration with Lilly to create novel oncology medicines. The collaboration includes a co-development and co-commercialization agreement for Foghorn’s Selective BRM oncology program and an additional undisclosed oncology target. In addition, the collaboration includes three discovery programs using Foghorn’s proprietary Gene Traffic Control platform. Full Year 2023 Financial Highlights Collaboration Revenues. Collaboration revenues were $34.2 million for the year ended December 31, 2023, compared to $19.2 million for the year ended December 31, 2022. The increase year-over-year was primarily driven by revenue recognized under the Merck collaboration due to the termination of the agreement and the subsequent recognition of the remaining deferred revenue.Research and Development Expenses. Research and development expenses were $109.7 million for the year ended December 31, 2023, compared to $105.6 million for the year ended December 31, 2022. This increase was primarily due to costs associated with continued investment in R&D personnel, platform, and other early-stage research, partially offset by a decrease in spend on FHD-286 and FHD-609.General and Administrative Expenses. General and administrative expenses were $32.4 million for the year ended December 31, 2023, compared to $30.7 million for the year ended December 31, 2022. This increase was primarily due to an increase in investments to support the growing business, which included increases in personnel-related costs and stock-based compensation expense.Net Loss. Net loss was $98.4 million for the year ended December 31, 2023, compared to a net loss of $108.9 million for the year ended December 31, 2022.Cash, cash equivalents and marketable securities. As of December 31, 2023, the Company had $234.1 million in cash, cash equivalents and marketable securities, providing cash runway into the first half of 2026. About FHD-286 FHD-286 is a highly potent, selective, allosteric, and orally available small-molecule, enzymatic inhibitor of BRG1 (SMARCA4) and BRM (SMARCA2), two highly similar proteins that are the ATPases, or the catalytic engines, of the BAF complex, one of the key regulators within the chromatin regulatory system. In preclinical studies, FHD-286 has shown anti-tumor activity across a broad range of malignancies including both hematologic and solid tumors. About AMLAdult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow and the most common type of acute leukemia in adults. AML is a diverse disease associated with multiple genetic mutations. It is diagnosed in about 20,000 people every year in the United States. About FHD-909FHD-909 (a.k.a. LY4050784) is a highly potent, allosteric and orally available small molecule that selectively inhibits the ATPase activity of BRM (SMARCA2) over its closely related paralog BRG1 (SMARCA4), two proteins that are the catalytic engines across all forms of the BAF complex, one of the key regulators of the chromatin regulatory system. In preclinical studies, tumors with mutations in BRG1 rely on BRM for BAF function. FHD-909 has shown significant anti-tumor activity across multiple BRG1-mutant lung tumors. About Foghorn TherapeuticsFoghorn® Therapeutics is discovering and developing a novel class of medicines targeting genetically determined dependencies within the chromatin regulatory system. Through its proprietary scalable Gene Traffic Control® platform, Foghorn is systematically studying, identifying and validating potential drug targets within the chromatin regulatory system. The Company is developing multiple product candidates in oncology. Visit our website at www.foghorntx.com for more information on the company and follow us on X (formerly Twitter) and LinkedIn.Forward-Looking StatementsThis press release contains “forward-looking statements.” Forward-looking statements include statements regarding the Company’s clinical trials, product candidates and research efforts and other statements identified by words such as “could,” “may,” “might,” “will,” “likely,” “anticipates,” “intends,” “plans,” “seeks,” “believes,” “estimates,” “expects,” “continues,” “projects” and similar references to future periods. Forward-looking statements are based on our current expectations and assumptions regarding capital market conditions, our business, the economy and other future conditions. Because forward-looking statements relate to the future, by their nature, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. As a result, actual results may differ materially from those contemplated by the forward-looking statements. Important factors that could cause actual results to differ materially from those in the forward-looking statements include regional, national or global political, economic, business, competitive, market and regulatory conditions, including risks relating to our clinical trials and other factors set forth under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the Securities and Exchange Commission. Any forward-looking statement made in this press release speaks only as of the date on which it is made. Condensed Consolidated Balance Sheets(In thousands) Dec. 31, 2023 Dec. 31, 2022Cash, cash equivalents and marketable securities$234,057 $345,798Collaboration receivable — —All other assets 51,859 59,085Total assets$285,916 $404,883Deferred revenue, total$302,665 $336,820All other liabilities 60,441 67,951Total liabilities 363,106 404,771Total stockholders’ equity (77,190) 112Total liabilities and stockholders’ equity$285,916 $404,883 Condensed Consolidated Statements of Operations(In thousands, except share and per share amounts) Twelve Months Ended December 31, 2023 2022 Collaboration revenue$34,155 $19,228 Operating expenses: Research and development 109,689 105,618 General and administrative 32,372 30,747 Total operating expenses 142,061 136,365 Loss from operations (107,906) (117,137)Total other income, net 13,706 8,255 Loss before income taxes (94,200) (108,882)Provision for income taxes (4,226) — Net loss$(98,426) $(108,882)Net loss per share attributable to common stockholders—basic and diluted$(2.34) $(2.62)Weighted average common shares outstanding—basic and diluted 41,974,484 41,591,433 Contacts:Greg Dearborn, Foghorn Therapeutics Inc. (Investors) gdearborn@foghorntx.com Karin Hellsvik, Foghorn Therapeutics Inc. (Investors and Media) khellsvik@foghorntx.com Adam Silverstein, ScientPR (Media) adam@scientpr.com Peter Kelleher, LifeSci Advisors (Investors) pkelleher@lifesciadvisors.com