作者: Xu, Shengtao ; Chen, Jichao ; Duan, Yiping ; Chen, Long ; Zhou, Pijun ; He, Chen ; Yao, Hong ; Zhong, Wenyi ; Xu, Jinyi ; Zhang, Baixue ; Wang, Tianyi

Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T cell receptor signaling, plays a crucial role in multiple cellular immune responses. Emerging researches have demonstrated that inhibiting HPK1 kinase function enhances T cells' ability to recognize tumor antigens and boosts anti-tumor immune responses. As a result, HPK1 has become a promising target for tumor immunotherapy. Herein, we report the design, synthesis, and biological evaluation of a series of novel HPK1 inhibitors featuring a 3-cyano-quinoline scaffold. Among these, compound 3a was identified as the most potent HPK1 inhibitor (HPK1 IC₅₀ = 48 nM). It effectively inhibited SLP76 phosphorylation, enhanced IL-2 cytokine secretion, and reversed PGE2-induced immunosuppression in Jurkat cells. In addition, compound 3a exhibited favorable metabolic stability in mouse liver microsomes and plasma. Overall, this work provides a structurally novel lead compound for the development of HPK1 inhibitors.

项与 HPK1 Inhibitor(Curadev Pharma ) 相关的新闻（医药）

2024-03-06

·BioSpace

Cardiff Oncology Announces Upcoming Presentations at the AACR Annual Meeting 2024

SAN DIEGO, March 06, 2024 (GLOBE NEWSWIRE) -- Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company leveraging PLK1 inhibition to develop novel therapies across a range of cancers, today announced publications of five abstracts that will be presented in a poster session at the American Association for Cancer Research (AACR) Annual Meeting, taking place from April 5-10, 2024, in San Diego, California. “The posters we will be presenting at this year’s AACR meeting represent a broad view of the potential of onvansertib in several different cancer indications, including RAS-mutant mCRC, RAS-wild type mCRC, small cell lung cancer and ovarian cancer,” said Mark Erlander, Ph.D., Chief Executive Officer of Cardiff Oncology. “In RAS-mutated mCRC, we are showing the underlying mechanism through which the combination of onvansertib and bevacizumab targets the hypoxia response pathway. We believe this mechanism explains the strong clinical results we have seen in both our Phase 1b/2 and ONSEMBLE second-line RAS-mutated mCRC clinical trials. The additional posters provide new insights and rationale for future clinical trials in other cancer indications.” Details on the posters and corresponding abstracts are shown below. Poster Title: A phase 1b/2 clinical study of onvansertib in combination with FOLFIRI/bevacizumab revealed a new role of PLK1 in regulating the hypoxia pathway in KRAS-mutant colorectal cancer Session Title: Microenvironment, Immunity, and DNA Repair in Therapeutic Response Session Date and Time: Monday Apr 8, 2024: 9:00 AM - 12:30 PM PT Location: Poster Section 27, Poster Board #14, Abstract Number #2031 This abstract presents updated clinical data and biomarker analysis from the Phase 1b/2 study evaluating onvansertib in combination with FOLFIRI/bevacizumab for second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC) patients. Analysis of patient baseline characteristics revealed superior clinical benefit in patients not exposed to bevacizumab in first-line treatment (Bev-naïve) compared to Bev-exposed patients. Bev-naive patients exhibited higher objective response rates (73.3% versus 15.7%) and longer median progression-free survival (14.9 versus 7.8 months) compared to Bev-exposed patients. Preclinical studies, using KRAS-mutant colorectal cancer mouse models revealed robust antitumor activity of onvansertib in combination with bevacizumab and a novel role of onvansertib in regulating tumor vascularization. Further preclinical investigations showed that PLK1 regulates the hypoxia pathway in KRAS-mutant CRC cells through the modulation of the hypoxia-inducible factor 1 alpha, HIF1α, emphasizing the potential crosstalk between PLK1 and angiogenesis. These findings reinforce the rationale for exploring onvansertib in combination with FOLFIRI/bevacizumab for Bev-naïve mCRC patients with KRAS mutation. Poster Title: The PLK1 inhibitor, onvansertib, is active as monotherapy and in combination with cetuximab in RAS wild-type colorectal cancer patient-derived xenografts Session Title: Drug Resistance 2: Ras GTPase Session Date and Time: Monday Apr 8, 2024: 9:00 AM - 12:30 PM PT Location: Poster Section 24, Poster Board #12, Abstract Number #1934 This abstract focuses on the preclinical assessment of onvansertib’s antitumor activity in RAS wild-type colorectal cancer, as both a monotherapy and in combination with cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Employing patient-derived xenograft (PDX) models, the study highlights the robust antitumor efficacy of onvansertib monotherapy, in cetuximab-sensitive and -resistant RAS wild-type colorectal cancer models. Furthermore, the combination of onvansertib and cetuximab was highly effective, resulting in tumor regression in 90% of the PDXs. These compelling data strongly support the clinical development of onvansertib as a potential treatment for RAS wild-type colorectal cancer. Poster Title: A phase 2, randomized, open-label study of onvansertib in combination with standard-of-care (SoC) versus SoC alone for first-line treatment of RAS-mutant metastatic colorectal cancer(mCRC) Session Title: Phase II and Phase III Clinical Trials in Progress Session Date and Time: Tuesday, Apr 9, 2024: 1:30 PM - 5:00 PM PT Location: Poster Section 50, Poster Board #5, Abstract Number #CT275 This abstract describes a clinical trial in progress. Poster Title: The PLK1 inhibitor, onvansertib, synergizes with paclitaxel in small cell lung cancer Session Title: Kinase and Phosphatase Inhibitors 1 Session Date and Time: Sunday Apr 7, 2024: 1:30 PM - 5:00 PM PT Location: Poster Section 25, Poster Board #16, Abstract Number #606 This abstract outlines preclinical studies showing the promising potential of combining onvansertib with paclitaxel for small cell lung cancer (SCLC). The research reveals significant synergy of the combination in SCLC cell lines and demonstrates its robust antitumor activity in patient-derived xenograft models, including models resistant to the standard therapy cisplatin. Further insights into the combination's mechanism of action will be presented. These findings support that combining onvansertib with paclitaxel could emerge as a highly promising treatment strategy for SCLC. Poster Title: In vivo anti-tumor activity of onvansertib, a PLK1 inhibitor, combined with gemcitabine or carboplatin in platinum-resistant ovarian carcinoma patient-derived xenograft models Session Title: Application of Precision Medicine for Cancer Care Session Date and Time: Sunday Apr 7, 2024: 1:30 PM - 5:00 PM PT Location: Poster Section 39, Poster Board #13, Abstract Number #945 This abstract explores preclinically the potential of combining onvansertib with the chemotherapeutic agents carboplatin or gemcitabine for platinum-resistant high-grade ovarian carcinoma. Using patient-derived xenografts, we demonstrated robust efficacy for both combinations, coupled with favorable tolerability. These data underscore the potential of onvansertib to improve the efficacy of the standard-of-care carboplatin and gemcitabine for patients with platinum-resistant high-grade ovarian carcinoma. The abstracts are available on the AACR Online Program and will be published in the online Proceedings of the AACR. Following presentation, the posters will be posted to the "Scientific Presentations" section of the Cardiff Oncology website. About Cardiff Oncology, Inc. Cardiff Oncology is a clinical-stage biotechnology company leveraging PLK1 inhibition, a well-validated oncology drug target, to develop novel therapies across a range of cancers. The Company's lead asset is onvansertib, a PLK1 inhibitor being evaluated in combination with standard-of-care (SoC) therapeutics in clinical programs targeting indications such as RAS-mutated metastatic colorectal cancer (mCRC) and metastatic pancreatic ductal adenocarcinoma (mPDAC), as well as in investigator-initiated trials in small cell lung cancer (SCLC) and triple negative breast cancer (TNBC). These programs and the Company's broader development strategy are designed to target tumor vulnerabilities in order to overcome treatment resistance and deliver superior clinical benefit compared to the SoC alone. For more information, please visit Cardiff Oncology Contact: James Levine Chief Financial Officer 858-952-7670 jlevine@cardiffoncology.com Investor Contact: Kiki Patel, PharmD Gilmartin Group 332-895-3225 Kiki@gilmartinir.com Media Contact: Richa Kumari Taft Communications 551 344-5592  richa@taftcommunications.com

临床2期临床结果ASCO会议AACR会议临床1期

2023-12-22

·BioSpace

Cyclacel Pharmaceuticals Announces Registered Direct and Private Placement Offering Priced At-The-Market Under Nasdaq Rules

BERKELEY HEIGHTS, N.J., Dec. 22, 2023 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; "Cyclacel" or the "Company"), a biopharmaceutical company developing innovative medicines based on cancer cell biology, announced today that it has entered into a definitive agreement for the purchase and sale of 388,200 shares of the Company’s common stock (or pre-funded warrants in lieu thereof) at a purchase price of $3.315 per share of common stock (or pre-funded warrant in lieu thereof) in a registered direct offering priced at-the-market under Nasdaq rules. The Company will also issue unregistered warrants to purchase up to 388,200 shares of common stock with an exercise price of $3.19 per share which will be immediately exercisable for a period of seven years following issuance. The closing of the offering is expected to occur on or about December 26, 2023, subject to the satisfaction of customary closing conditions. In a concurrent private placement, the Company will also issue an aggregate of 7,956 shares of common stock at the same purchase price of $3.315 per share and warrants to purchase up to 7,956 shares of common stock with an exercise price of $3.19 per share to members of management. Ladenburg Thalmann & Co. Inc. is acting as the exclusive placement agent for the offering. The gross proceeds from the offering, before deducting the placement agent's fees and other offering expenses, are expected to be approximately $1.3 million. The Company intends to use the net proceeds from this offering for working capital and general purposes. The shares of common stock, pre-funded warrants and shares of common stock underlying the pre-funded warrants (but not the warrants or the shares of common stock underlying the warrants) described above (other than the shares to be sold to members of management) are being offered pursuant to a “shelf” registration statement on Form S-3 (File No. 333-274328), previously filed with the Securities and Exchange Commission (the “SEC”) and declared effective on September 13, 2023. The offering of such shares of common stock and pre-funded warrants is made only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. A final prospectus supplement and accompanying prospectus relating to the registered direct offering will be filed with the SEC. Electronic copies of the prospectus supplement, when available, may be obtained on the SEC’s website at and may also be obtained by contacting Ladenburg Thalmann & Co. Inc., Prospectus Department, 640 Fifth Avenue, 4th Floor, New York, New York 10019 or by email at prospectus@ladenburg.com. The warrants described above are being offered in a private placement under Section 4(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”), and/or Regulation D promulgated thereunder and, along with the shares of common stock underlying the warrants, have not been registered under the Securities Act, or applicable state securities laws. Accordingly, the warrants and underlying shares of common stock may not be offered or sold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Securities Act and such applicable state securities laws. This press release shall not constitute an offer to sell or a solicitation of an offer to buy any of the securities described herein, 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 Cyclacel Pharmaceuticals, Inc. Cyclacel is a clinical-stage, biopharmaceutical company developing innovative cancer medicines based on cell cycle, transcriptional regulation, epigenetics and mitosis biology. The transcriptional regulation program is evaluating fadraciclib, a CDK2/9 inhibitor, and the epigenetic/anti-mitotic program plogosertib, a PLK1 inhibitor, in patients with both solid tumors and hematological malignancies. Cyclacel's strategy is to build a diversified biopharmaceutical business based on a pipeline of novel drug candidates addressing oncology and hematology indications. For additional information, please visit . Forward-looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and intended utilization of Cyclacel’s product candidates, the conduct and results of future clinical trials, plans regarding regulatory filings, future research and clinical trials and plans regarding partnering activities. Factors that may cause actual results to differ materially include, without limitation: interim results of a clinical trial are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and as more patient data becomes available, including the risk that unconfirmed responses may not ultimately result in confirmed responses to treatment after follow-up evaluations; the risk that product candidates that appeared promising in early research and clinical trials do not demonstrate safety and/or efficacy in larger-scale or later clinical trials; potential delays in the commencement, enrollment and completion of clinical trials; Cyclacel may not obtain approval to market its product candidates; the risks associated with reliance on outside financing to meet capital requirements; the potential effects of the COVID-19 pandemic; and the risks associated with reliance on collaborative partners for further clinical trials, development and commercialization of product candidates. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "believes," "estimates," "projects," "potential," "expects," "plans," "anticipates," "intends," "continues," "forecast," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to our most recent Annual Report on Form 10-K, as amended, and other periodic and other filings we the Securities and Exchange Commission and are available at . Such forward-looking statements are current only as of the date they are made, and we assume no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts Company: Paul McBarron, (908) 517-7330, pmcbarron@cyclacel.com Investor Relations: Grace Kim, IR@cyclacel.com © Copyright 2023 Cyclacel Pharmaceuticals, Inc. All Rights Reserved. The Cyclacel logo and Cyclacel® are trademarks of Cyclacel Pharmaceuticals, Inc.

100 项与 HPK1 Inhibitor(Curadev Pharma ) 相关的药物交易

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