IK-930 / ImageneBio - LARVOL DELTA

DrugAppy - An end-to-end deep learning framework for computational drug discovery. (PubMed, Comput Biol Med) - "For PARP1, two molecules were found with activity comparable to olaparib. For TEAD4, a compound was identified that outperforms the activity of IK-930, the reference inhibitor for this target. In this work, we demonstrate how the workflow can be effectively used to discover novel molecular structures, using the protein families PARP and TEAD as case studies. For each target, one active compound has been identified and confirmed for target engagement that matches the reference inhibitor."

Journal • Oncology • TEAD4

Validation of an AI-powered computational chemistry workflow for streamlined drug discovery (AACR-NCI-EORTC 2025) - "Of the 17 compounds tested in vitro, one molecule demonstrated potent activity (IC₅₀ = 1.31 nM), comparable to the clinically approved PARP1 inhibitor olaparib (IC₅₀ = 1.61 nM)...In the TEAD4 case study, 1 out of 8 selected compounds exhibited superior in vitro performance (IC₅₀ = 13–18 µM) compared to IK-930 (IC₅₀ = 25–158 µM), a known TEAD family inhibitor. Inhibition of canonical YAP/TAZ-TEAD transcriptional targets suggests that this compound acts as a pan-TEAD inhibitor, with strong binding affinity for both TEAD2 and TEAD4...These findings illustrate the power of the DrugAppy to identify and prioritize novel molecular scaffolds for targeted cancer therapy. The platform enables efficient early-stage drug discovery through the integration of AI, docking, and MD simulations, supporting the development of next-generation cancer therapeutics with improved rationality and speed."

Oncology • TEAD2 • TEAD4

Hippo/YAP signaling pathway in colorectal cancer: regulatory mechanisms and potential drug exploration. (PubMed, Front Oncol) - "Preclinical and clinical investigations highlight the efficacy of diverse Hippo/YAP-targeted interventions, with recent clinical trials (e.g., VT3989, IK-930, IAG933, ION537) underscoring the translational promise of this pathway. Integrating cutting-edge insights into its regulatory networks and clinical targeting offers novel perspectives for precision oncology. By bridging fundamental discoveries with translational applications, this review establishes Hippo/YAP as a compelling therapeutic target and provides a theoretical foundation for developing innovative CRC therapies."

Journal • Review • CNS Disorders • Colorectal Cancer • Oncology • Psychiatry • Solid Tumor • TAFAZZIN

Combination therapy targeting genomic and signal transduction vulnerabilities in epithelioid hemangioendothelioma (AACR 2025) - "Because most EHE cells contain either the TAZ-CAMTA1 or YAP-TFE3 fusion proteins that activate a transcriptome that promotes several hallmarks of cancer, targeting the main way the fusions interact with DNA could mitigate these effects. Previous studies investigating the use of monotherapies to target cells expressing the fusion proteins show limited effectiveness. However, targeting both the interaction of the fusion proteins' ability to interact with DNA as well as an important pathway for EHE cells, such as the PI3K pathway, could lead to a greater effectiveness in decreasing EHE tumor progression."

Combination therapy • Liposarcoma • Oncology • Sarcoma • Solid Tumor • CAMTA1 • TAFAZZIN • TFE3

PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted. (PubMed, bioRxiv) - "Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage independent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. TAZ and YAP are transcriptional co-activators downstream of PI3K signaling, a pathway that has lacked a well-defined oncogenic transcription factor. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis allowing for synergistic combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1 in sarcomas."

Journal • Oncology • Sarcoma • Solid Tumor • PTEN

Oral TEAD Inhibitor Targeting the Hippo Pathway in Subjects with Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=67 | Terminated | Sponsor: Ikena Oncology | N=198 ➔ 67 | Trial completion date: Jun 2025 ➔ Sep 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jun 2025 ➔ Aug 2024; Sponsor strategic reasons

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Cholangiocarcinoma • Hepatocellular Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAMTA1 • TAFAZZIN • TFE3 • YAP1

Oral TEAD Inhibitor Targeting the Hippo Pathway in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=198 | Active, not recruiting | Sponsor: Ikena Oncology | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAMTA1 • TAFAZZIN • TFE3 • YAP1

Advances in Targeted Therapy for Malignant Pleural Mesothelioma (PubMed, Zhongguo Fei Ai Za Zhi) - "At present, it has been found the following types of targets: gene mutation targets such as BRCA associated protein 1 (BAP1) and cyclin-dependent kinase 2A (CDKN2A); epigenetic targets such as lysine (K)-specific demethylase 4A (KDM4A) and lysine-specific demethylase 1 (LSD1), and signal protein targets such as glucose-regulated protein 78 (GRP78) and signal transducer and activator of transcription 3 (STAT3). So far, available clinical trials include phase II clinical trials of histone methyltransferase inhibitor Tazemetostat, poly (ADP-ribose) polymerase (PARP) inhibitor Rucaparib and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib, as well as phase I clinical trials of mesothelin-targeting chimeric antigen receptor T-cell immunotherapy (CAR-T) cell injection in the thoracic cavity and TEA domain family member (TEAD) inhibitor VT3989 and IK-930, and the results of these trials have showed certain clinical efficacy.."

IO biomarker • Journal • Review • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • BAP1 • BRCA • CDKN2A • HSPA5 • KDM4A • MSLN • STAT3

Ikena Oncology Announces Strategic Update (GlobeNewswire) - "Based on a review of clinical data to date, available resources, and the Company’s strategic priorities, the Company decided to discontinue development of IK-930. The IK-930 Phase 1 program will begin wind down activities; treatment will continue for patients enrolled to date who have derived benefit. The Company will seek strategic options for the program, including potential partners for development of IK-930 in combination with other targeted agents."

Discontinued • Trial termination • Solid Tumor

TEAD1/4 inhibitors exhibit deeper biological impact and broader activity compared to TEAD1-only inhibitors in both monotherapy and combination without additional kidney toxicity (AACR 2024) - "However, the TEAD1-preferential inhibitor IK930 did not yield any objective responses but also showed a more favorable safety profile especially with respect to proteinuria. We show that 1) SPR1 displays broader and deeper cell-based activity and extends the utility of TEAD inhibitors outside of mesothelioma and NF2 mutants 2) SPR1 shows stronger activity than TEAD1-only inhibitors in combination with MAPK and EGFR inhibitors in vitro and in vivo 3) SPR1 does not cause proteinuria in mice; dogs or rats even above therapeutic doses 4) SPR1 does not show the context-specific stimulation of tumor growth in Lung PDX previously observed with VT3989 and other inhibitors that include TEAD2 in their profile. Taken together - the data suggests SPR1 is positioned to become a best-in-class TEAD palmitic acid site inhibitor with broad utility in both monotherapy and combination setting."

Monotherapy • Mesothelioma • Oncology • Solid Tumor • NF2 • TEAD1 • TEAD2 • TEAD3

Oral TEAD Inhibitor Targeting the Hippo Pathway in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=198 | Recruiting | Sponsor: Ikena Oncology | Trial completion date: Oct 2024 ➔ Jun 2025 | Trial primary completion date: Oct 2024 ➔ Jun 2025

Metastases • Trial completion date • Trial primary completion date • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAMTA1 • TAFAZZIN • TFE3 • YAP1

Harnessing the power of endogenous metabolite-protein interactions for allosteric modulation (ACS-Sp 2024) - "Allosteric metabolite binding sites on these targets have been successfully used to generate new medicines (e.g.: Asciminib for BCR-ABL) and investigational cancer therapies (e.g.: IK-930, VT3989 for TEAD). Atavistik Bio has developed the AMPS (Atavistik Metabolite Protein Screening) platform that enables systematic and scalable screening of metabolites against proteins or protein complexes of interest. In this oral presentation, it will be highlighted how the AMPS platform can identify allosteric protein-metabolite interactions to advance small molecule drug discovery efforts."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR

Ikena Oncology Reports Fourth Quarter and Full Year 2023 Financial Results (GlobeNewswire) - "IK-930: A clinical data update is planned for the second half of 2024 and will include additional data from EHE patients and first data from mesothelioma patients."

P1 data • Mesothelioma • Oncology

Ikena Oncology Shares Initial Positive and Differentiated Dose Escalation Data from IK-930 Phase I Trial and Reports Third Quarter 2023 Financial Results (Ikena Oncology Press Release) - "Based on preclinical data indicating IK-930 synergy with EGFR inhibitors to combat therapeutic resistance, a combination cohort for IK-930 and osimertinib in patients with EGFR-mutant non-small cell lung cancer (NSCLC) is planned to initiate in 2024. An additional data update from the IK-930 clinical program is planned for the second half of 2024."

P1 data • Trial status • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Ikena Oncology Reports Second Quarter 2023 Financial Results and Corporate Update (GlobeNewswire) - "IK-930: The ongoing Phase 1 study is progressing as planned and has advanced through multiple dose escalation cohorts, which will be included in the initial clinical data update planned for the fourth quarter of 2023."

P1 data • Oncology • Solid Tumor

Ikena Oncology Acquires Pionyr Immunotherapeutics in All-Stock Transaction (GlobeNewswire) - "Ikena Oncology, Inc...and Pionyr Immunotherapeutics, Inc...announced the closing of Ikena’s acquisition of Pionyr in an all-stock transaction. Ikena acquired all of Pionyr’s assets, including approximately $43 million in net cash, in exchange for shares of IKNA stock, in a combination of common stock and non-voting convertible preferred stock priced at $7.15 per share....The transaction further strengthens Ikena’s financial position as the Company advances development of its targeted oncology programs. The new capital will enable Ikena to expand and accelerate its targeted oncology programs, including both IK-930, Ikena’s clinical program targeting the Hippo pathway with initial clinical data expected this year, and IK-595, a MEK-RAF complexing inhibitor expected to have an IND submitted this year."

IND • M&A • Oncology

Ikena Oncology Reports First Quarter 2023 Financial Results and Highlights Advancements Across Targeted Oncology Pipeline (GlobeNewswire) - "Initial clinical data from the monotherapy portion of the ongoing Phase 1 clinical trial of IK-930, including patients from the dose escalation cohorts and backfilling, is planned for the fourth quarter of 2023....Investigational new drug (IND) application submission for IK-595 planned for the second half of 2023....IK-175: AHR Inhibitor in Collaboration with Bristol Myers Squibb...The Phase 1 clinical trial in urothelial carcinoma has completed enrollment; treatment is ongoing and the program is eligible for opt-in from Bristol Myers Squibb through early 2024."

Enrollment closed • IND • P1 data • Genito-urinary Cancer • Mesothelioma • Oncology • Solid Tumor • Urothelial Cancer

Ikena Oncology Announces $40 Million Underwritten Offering (GlobeNewswire) - "Ikena Oncology, Inc...announced today the pricing of an underwritten offering of 6,110,000 shares of common stock (the “Shares”) at an offering price of $6.55 per share....The offering is expected to close on or about May 17, 2023, subject to satisfaction of customary closing conditions. The Company anticipates the net proceeds of the offering, together with existing cash, cash equivalents and investments, to further its ongoing clinical development of targeted oncology programs and advance them to clinical data read outs beyond the initial data for the monotherapy portion of the ongoing IK-930 Phase 1 clinical trial in the fourth quarter of 2023 and initial clinical data for IK-595, in addition to working capital, capital expenditures and other general corporate purposes."

Financing • P1 data • Mesothelioma • Oncology • Solid Tumor

IK-930, a paralog-selective novel TEAD-inhibitor, effectively attenuates drug-tolerant persister cell proliferation (AACR 2023) - "We showed that combining the novel, paralog selective TEAD inhibitor, IK-930, with osimertinib or trametinib in EGFR or KRAS mutated tumors, led to enhanced apoptosis in vitro and beneficial antitumor activity in vivo. Concurrent addition of IK-930, as well as addition of IK-930 after the emergence of the osimertinib-tolerant persister cells, attenuated cell proliferation and expansion, demonstrating the potential for IK-930 to prevent resistance to EGFR inhibitors and even reverse the effect when given after resistance has already emerged. Current efforts are focused on the characterization of the persister population and on evaluating the role of YAP/TEAD signaling in resistance to other targeted therapies."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • YAP1

TY-0584: A potent, orally available small molecule YAP/TEAD inhibitor, exhibits anti-tumor effects in vitro and in vivo (AACR 2023) - P1, P3 | "Therefore, small molecules that target palmitoylation of TEAD have been explored and VT3989 (NCT04665206) and IK-930 (NCT05228015) have success to enter the clinical trials...In line with the results of the in-vitro experiments, another YAP/TEAD inhibitor TY-0536 in combination with TY-9591 significantly delay the tumor regrowth in the PC9 CDX mouse model...[Shengli Dong and Apeng Liang contributed equally to this work. Jun Li, Shengli Dong, and Apeng Liang are the corresponding authors.]"

Preclinical • Brain Cancer • CNS Tumor • Head and Neck Cancer • Lung Cancer • Melanoma • Meningioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • NF2

Single and combined inhibition of PAK and Hippo pathway in NF2-deficient schwannoma (AACR 2023) - "Using several YAP-TEAD binding inhibitors (TED-347, NSC682769, IK-930), Group I PAK inhibitors (FRAX-1036, G555) and PAK1-specific inhibitor (NVS-1-PAK1) we found that YAP-TEAD binding inhibition combined with Group I PAK inhibition has the greatest reduction on Schwannoma cell viability, proliferation, and increase in cell death. Taken together, our findings indicate that both the Hippo pathway and PAK proteins may be viable targets for Schwannoma therapies. Furthermore, combining the two may lead to a synergistic effect and further prevent growth of NF2-deficient Schwannomas."

Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor

IK-930, a paralog-selective TEAD inhibitor for treating YAP/TAZ-TEAD dependent cancers (AACR 2023) - "Collectively, these results suggest that paralog selectivity with IK-930 broadens the therapeutic window of this novel compound class. With its distinct TEAD inhibitory profile, IK-930 offers unique therapeutic index advantages, further supporting its development as a first-in-class paralog-selective TEAD inhibitor."

Oncology • TAFAZZIN • TEAD1

Ikena Oncology to Participate in the Stifel 2023 Virtual Targeted Oncology Days (GlobeNewswire) - "Ikena’s Chief Executive Officer, Mark Manfredi, Ph.D., will present a corporate overview on Tuesday, April 25 highlighting advancements across the company’s pipeline of targeted oncology programs, including recent preclinical data shared at AACR 2023 Annual Meeting around the differentiation profile of IK-930, the company’s novel Hippo pathway inhibitor that selectively binds and inhibits TEAD1."

Preclinical • Oncology

Ikena Oncology Shares Differentiation Profile of IK-930, a Novel Hippo-Pathway Inhibitor, Including Projected Therapeutic Index Advantages and Breadth of Patient Populations at AACR 2023 Annual Meeting (GlobeNewswire) - "Highlights from the data in today’s poster include: In nonclinical models and species, IK-930 demonstrated selective inhibition of TEAD1 with equivalent activity to broad TEAD inhibitors and a significantly improved tolerability profile. IK-930 promotes repressive TEAD1 activity by driving interactions with VGLL4, a signaling partner that reduces expression of pro-growth and anti-apoptotic genes. Through its binding with TEAD1 and VGLL4, IK-930 potentially blocks chromatin binding of other TEAD paralogs...In addition, tomorrow the Company will present a poster that highlights IK-930’s ability to reduce and reverse resistance to other targeted therapies in preclinical models. Highlights include: Treatment with IK-930 in combination with multiple targeted agents, such as EGFR, KRAS G12C, and MEK inhibitors, demonstrated a reduction in emergence of drug resistant 'persister' cells."

Preclinical • Oncology

Ikena Oncology Reports Fourth Quarter and Full Year 2022 Financial Results (GlobeNewswire) - "Phase 1 trial of IK-930 in Hippo altered cancers (NCT05228015) continues to advance as expected, with multiple dose escalation cohorts cleared....Initial clinical data from the monotherapy portion of the Phase 1 study is expected in the second half of 2023....Investigational new drug application (IND) submission for IK-595 to the U.S. Food & Drug Administration (FDA) planned for the second half of 2023. IK-175: AHR Inhibitor in Collaboration with Bristol Myers Squibb....The program is eligible for opt-in from Bristol Myers Squibb through early 2024."

IND • P1 data • Genito-urinary Cancer • Mesothelioma • Oncology • Solid Tumor • Urothelial Cancer