Supplementary Figure S1. AZD4547 shows a moderate FLT3 inhibition and no DDR1 inhibition in cells. Supplementary Figure S2. AZD4547 moderately inhibited p-GSK3� in both AN3-CA and MFE296 cells. Supplementary Table S1. Primer sequences for RT-PCR analysis Supplementary Table S2. in vitro inhibition profiling of AZD4547 at 1 μΜ against 336 human kinases Supplementary Table S3. Upregulated genes in (DMSO+aFGF)-treated AN3-CA cells compared with the DMSO-treated cells (18 h) Supplementary Table S4. Down regulated genes in (AZD4547+aFGF)-treated AN3-CA cells compared with the (DMSO+aFGF)-treated cells (18 h) Supplementary Table S5. Genes in the downstream of FGFR2

Melanoma, an aggressive skin cancer caused by BRAF or NRAS mutations, is characterized by the hyperactivation of the MAPK pathway. Despite the initial clinical success of RAF and MEK inhibitors in BRAF V600E-mutant melanoma, resistance mechanisms, including MAPK pathway reactivation, compromise their efficacy. This study investigated PHI-501, a next-generation pan-RAF/DDR dual inhibitor, as a potential strategy for overcoming this resistance. The anti-proliferative activity of PHI-501 was evaluated in parental and acquired drug-resistant melanoma cell lines and compared with clinically relevant RAF inhibitors. Mechanistic studies included analyses of ERK, AKT, and DDR1/2 phosphorylation, as well as transcriptomic profiling of resistance-associated pathways. In vivo efficacy was assessed using xenograft models of SK-MEL-3 melanoma cells with acquired resistance to dabrafenib alone or to combined dabrafenib plus trametinib treatment. PHI-501 exhibited greater cytotoxic activity than conventional RAF inhibitors in acquired drug-resistant melanoma cells. PHI-501 suppressed MAPK and PI3K/AKT signaling, as evidenced by reduced phosphorylation of ERK, AKT, and DDR1/2. Transcriptomic profiling revealed coordinated downregulation of key resistance-associated signaling pathways. In xenograft models derived from melanoma cells resistant to RAF inhibitor monotherapy or combined RAF/MEK inhibition, PHI-501 significantly inhibited tumor growth. PHI-501 exhibited potent anti-tumor activity in models of drug-resistant melanoma through dual targeting of RAF and DDR1/2. These findings support further preclinical evaluation of PHI-501 for MAPK inhibitor–resistant melanoma.

KRAS is one of the most frequently mutated oncogenes in human cancers, with KRAS G12D representing the predominant mutation in pancreatic ductal adenocarcinoma and a major driver of colorectal and lung cancers. Although KRAS was long considered "undruggable" due to structural and biochemical constraints, the discovery of the switch-II pocket enabled the development of direct KRAS inhibitors, leading to the clinical success of KRAS G12C-targeted therapies. Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805. Pan-RAS and pan-KRAS inhibitors have emerged as a promising strategy to overcome the limitations of mutation-specific KRAS inhibitors, including restricted mutation coverage and acquired resistance. Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment.

Mutations and rearrangements of Rearranged during Transfection kinase (RET) are highly implicated with thyroid cancer. This study aimed to explore the therapeutic potential of a targeted protein degradation (TPD) strategy against RET-associated medullary thyroid carcinoma (MTC). The investigation of the structure-activity relationship (SAR) led to the identification of a novel RET-CRBN degrader, JW15 which possesses excellent degradation capability (DC50 = 0.3 nM) and potent anti-proliferative activity (GI50 = 1.2 nM) on TT cells (MTC). Mechanistic studies revealed that JW15 degrades RET kinase via the ubiquitin-proteasome system (UPS) and effectively recruits cereblon (CRBN) E3 ligase in target engagement assays. Notably, JW15 exhibited superior suppression of RET phosphorylation and downstream signaling compared with selpercatinib. In addition, JW15 demonstrated greater efficacy than selpercatinib in inducing apoptosis and suppressing colony-forming capacity on TT cells, particularly at a concentration of 1 nM. JW15 administered intravenously at 20 mg/kg twice weekly demonstrated significant antitumor efficacy, showing 70% tumor growth inhibition in RET Ba/F3 xenograft models over 13 days. Taken together, our study provides fundamental guidelines for structure-guided design and optimization for the development of RET degraders, offering a promising strategy for targeting RET-driven cancers.

The IL-33/ST2 signaling axis plays a crucial role in shaping the tumor microenvironment, primarily by promoting immune suppression through tumor-infiltrating regulatory T (Treg) cells. Elevated IL-33 levels are associated with poor prognosis in multiple cancers, as IL-33 enhances Treg stability, proliferation, and suppressive function, thereby dampening antitumor immunity. In this study, we present the rational design and biological evaluation of novel small-molecule inhibitors targeting IL-33/ST2 signaling to suppress Treg-mediated immune evasion. Guided by structure-based drug design, we identified oxazolo[5,4-d]pyrimidine derivatives capable of forming key hydrogen bonds within the IL-33 binding pocket, thereby enhancing binding affinity. In vitro and ex vivo assays using T-Cell Receptor(TCR)-stimulated human Treg cells demonstrated that these compounds significantly suppressed IL-33-induced Treg activation and proliferation. Notably, KYH1942 showed the most potent activity, reducing IL-33-induced Foxp3 and Ki-67 expression in a dose-dependent manner, indicative of impaired Treg function. It is worth noting that the inhibitory activities of our compounds are comparable to that of a neutralizing ST2 antibody. To our knowledge, this is the first report demonstrating that small-molecule IL-33 blockade can directly suppress Tregs, including IL-33-driven Foxp3 and Ki-67 expression. These findings establish a novel immunotherapeutic strategy targeting IL-33-mediated immune suppression.

Background: Lysosomal dysfunction could be an underlying cause of Alzheimer's disease, with Tau oligomer being an important inducer or amplifier of lysosomal stress associated with the disease. Tau oligomer is a well-known substrate of autophagy, and selective degradation of Tau with Tau-specific autophagy degrader might be feasible. Methods: Tau-specific autophagic degraders were synthesized by combining leucomethylene blue, linkers and a lysosomal degradation tag (Autac). Tau clearance and changes of Tau-mediated lysosomal stress by these degraders were studied in vitro. In vivo effects of a Tau-specific degrader were investigated employing a combined Tau/Aβ mutant mouse model characterized by an accelerated onset of neurological deficits. Human relevance was investigated using induced pluripotent stem cell (iPSC)-derived neuronal cells from an Alzheimer's disease patient. Results: Among Tau-specific Autac degraders, TauAutac-3 (TA-3) efficiently degraded Tau oligomer and monomer, an effect inhibited by bafilomycin A1, suggesting lysosomal Tau degradation. TA-3 treatment induced LC3, K63, OPTN or NDP52 puncta, which was partially colocalized with Tau oligomer. Signs of lysosomal stress, such as galectin-3 puncta, pHluorin fluorescence, altered lysosomal pH and CHMP2B recruitment, induced by Tau expression were reversed by TA-3. Autophagy impairment by Tau expression in vitro, likely due to lysosomal stress, was also reversed by TA-3. In vivo, TA-3 administration markedly reduced the accumulation of both Tau and Aβ in 6xTg mice, which was associated with amelioration of Tau-mediated lysosomal stress and autophagy impairment. Neuroinflammation characterized by increased numbers of GFAP+ glial cells and Iba1+ microglial cells, was also reduced following TA-3 administration. TA-3 remarkably improved neurologic deficits in 6xTg mice, such as impaired memory and reduced exploratory behavior. TA-3 reduced Tau and phospho-Tau accumulation in iPSC-derived neuronal cells from an Alzheimer's disease patient. Conclusion: These results suggest that Tau-specific autophagic (Autac) degraders could serve as novel therapeutic agents for Alzheimer's disease through reduction of Tau-mediated lysosomal stress.

KRASG12D is the most prevalent KRAS mutant in various cancers. We report the KRASG12D selective PROTAC, CH091138 (6), identified through SAR studies. 6 selectively degrades exogenous and endogenous KRASG12D but not KRASWT or other KRAS mutants. Furthermore, global proteomic analysis shows that KRAS is most significantly downregulated in AsPC-1 cells. Mechanistic studies reveal that the degradation depends on the VHL-mediated ubiquitin-proteasome system. The binding site of 6 was identified by NMR studies, and docking studies explain 6-mediated interaction between KRASG12D and VHL leads to KRASG12D selectivity. 6 suppresses the proliferation of AsPC-1 cells and the growth of colon cancer patient-derived organoids (PDOs) harboring KRASG12D but not PDOs with KRASWT. Notably, 6 reduces tumor growth in an AsPC-1 xenograft mouse model. Collectively, we report KRASG12D selective PROTAC and propose potential hypotheses for the selectivity. Also, our study reveals that PROTAC-mediated degradation of KRASG12D is an attractive anti-cancer strategy.

Being a primary driver in oncogenic activations of JAK-STAT signaling pathway, Janus Kinase 1 (JAK1) stands out as a promising target in anti-cancer drug discovery. We employed a scaffold morphing strategy to design and synthesize thieno[3,2-d]pyrimidine derivatives, which led to identification of 24 as a potent and highly selective JAK1 inhibitor. Kinome-wide selectivity profiling reveals that 24 exhibits a high degree of selectivity for JAK1 among the 370 kinases tested. SAR study demonstrates that both 25 and 46, improved derivatives of 24, possess higher selectivity towards JAK1 over JAK2 and JAK3 compared to AZD4205 (9). It is of note that 46 has 4-fold higher enzymatic activity against JAK1 (IC50 = 0.022 mu M) relative to 9. Moreover, both 25 and 46 demonstrate over 5-fold enhancement in anti-proliferative activities on NSCLC cells with regard to 9, accompanied by significant inhibition of JAK1 signaling. Compared with 9, derivative 24, 25, and 46 induce more strongly apoptosis, cell cycle arrest, and reduction of colony formation on NSCLC cells. Our findings offer valuable insights into the design of novel selective JAK1 inhibitors.

We discovered novel small molecule ligands of KLHDC2 and leveraged them to generate KLHDC2-mediated CDK6-selective degraders. Degrader 48a exhibited potent and selective CDK6 degradation (DC50 = 0.037 μM) over CDK4 (DC50 > 10 μM) in MOLM-14 cells, leading to pronounced G0/G1 cell-cycle arrest and apoptosis through inhibition of CDK6 downstream signaling. In addition, 48a demonstrated superior growth-inhibitory activity compared to the warhead, palbociclib, in several leukemia cells and displayed favorable microsomal stability. Proteomic profiling confirmed that 48a selectively degrades CDK6 with minimal effects on other CDK family members. Furthermore, 48a reduced tumor burden and CDK6 levels in an in vivo xenograft model. Collectively, these findings highlight the potential of KLHDC2-mediated degraders as a novel strategy for selective CDK6 degradation and underscore the promise of KLHDC2 as an alternative E3 ligase platform for targeted protein degradation.

Cholangiocarcinoma (CCA) is a diverse group of epithelial malignant tumors arising from the biliary tract, characterized by high molecular heterogeneity. It is classified into intrahepatic (iCCA) and extrahepatic CCA (eCCA) based on the location of the primary tumor. CCA accounts for approximately 15% of all primary liver cancers, with iCCA comprising 10-20% of all CCAs. iCCA is especially known for its characteristic aggressiveness and refractoriness, leading to poor prognosis. Despite the increasing global incidence and mortality rates, surgery remains the only available standard treatment approach for a subset (25%) of patients with early-stage, resectable iCCA. The paucity of effective systemic medical therapies restricts therapeutic options for patients with advanced or metastatic iCCA. In the past decade, advances in the understanding of the molecular complexity of these tumors have provided fruitful insights for the identification of promising new druggable targets and the development of feasible therapeutic strategies that may improve treatment outcomes for patients with iCCA. In this review, we aim to highlight critical up-to-date studies and medicinal chemistry aspects, focusing on novel targeted approaches utilizing promising candidates for molecular targeted therapy in iCCA. These candidates include aberrations in isocitrate dehydrogenase (IDH) 1/2, fibroblast growth factor receptor (FGFR), B-Raf proto-oncogene (BRAF), neurotrophic tyrosine receptor kinase (NTRK), human epidermal growth factor receptor 2 (HER2), and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1). Furthermore, this review provides an overview of potential inhibitors aimed at overcoming acquired drug resistance in these actionable targets for iCCA.

There are four generations of tyrosine kinase inhibitors (TKIs) that target BCR-ABL1 mutations, a fusion oncogene, in chronic myeloid leukaemia, but predicting the resistance profiles of these TKIs for patients with ABL1 mutations is sometimes difficult, especially when the mutations are not included by clinical guidelines. Here we use prime editing to generate 97% (2,802/2,892) of all possible single-nucleotide variants in the sequence encoding the ABL1 kinase domain, which covers 98% (1,954/1,998) of all possible corresponding single amino acid variants. We evaluated their effects on resistance to five TKIs (imatinib, nilotinib, bosutinib, ponatinib and asciminib), spanning all four TKI generations by using K562 cells. We identified 361 pairs of resistance-conferring single amino acid variants and the corresponding TKIs. Our comprehensive resistance map will complement clinical guidelines in drug selection for patients with chronic myeloid leukaemia based on ABL1 mutations, facilitating precision medicine.

Necroptosis, a form of programmed cell death, has emerged as a promising therapeutic target. Although several RIPK1 inhibitors have demonstrated favorable safety profiles in clinical trials, clinical translation of necroptosis-targeted therapies remains limited by modest efficacy, limited specificity, and species-specific activity of compounds such as necrosulfonamide (NSA). To resolve these challenges, this study identified a potential necroptosis inhibitor from a clinical drug library. Apomorphine (APO), a non-addictive morphine derivative used to treat Parkinson’s disease, was found to inhibit necroptosis by sterically blocking key residues involved in mixed lineage kinase domain-like protein (MLKL) activation and oligomerization, as confirmed by nuclear magnetic resonance analysis. APO is redox sensitive and prone to auto-oxidation. The oxidized form of APO (Ox-APO) showed stronger binding to MLKL than the reduced form of APO (Re-APO), as demonstrated by surface plasmon resonance analysis. Ox-APO significantly ameliorated tissue damage in two murine necroptosis models: dextran sulfate sodium (DSS)-induced colitis and acetaminophen (APAP)-induced liver injury. Collectively, these data highlight the therapeutic potential of APO as a necroptosis-specific inhibitor in necroptosis-related diseases in both humans and mice.

Cancer, driven by mitochondrial and nuclear DNA mutations, presents opportunities for targeted therapies. Gastric cancer (GC), the 4th leading cause of cancer-related deaths, has poor prognosis due to cancer stem cells (CSCs), which depend on mitochondrial complex II (CII) respiration. Among CSC-enriched subtypes, the aggressive stem-like/EMT/Mesenchymal (SEM) GC subtype exhibits high plasticity, chemotherapy resistance, and metabolic adaptations that promote tumor survival. This study explores α-d-tocopherol derivatives targeting GC cells with enriched cancer stemness (S-cells) by inhibiting succinate dehydrogenase (SDH), also known as the CII complex. Malonate (10) and primary amide (17) derivatives of α-D-tocopherol showed potent anti-proliferative activities in S-cells, with GI50 values of 0.203 μM (SSNU638) and 0.156 μM (SSK4), respectively, over 10-fold more potent than α-TOS (6). Mechanistic studies showed that both 10 and 17 inhibit SDHC activity, reduce CII-specific oxygen consumption rates (OCR), and induce increased ROS production, leading to apoptosis. Furthermore, in patient-derived organoid (PDO) models, derivative 10 (GA265T GI50 = 5.623 μM) and 17 (GA265T GI50 = 6.347 μM) exhibited enhanced anti-proliferative activity in SEM-type GC PDOs (SDHC-high) compared to non-SEM-type PDOs (SDHC-low), with over a 2-fold increase in anti-proliferative activity against the GA265T SEM-type PDO model compared to α-TOS (6; GA265T GI50 = 12.660 μM). In vivo studies further demonstrated that compound markedly inhibited tumor growth in SSK4 xenograft models with miniaml systemic toxicity, outperforming the reference compound α-TOS. These results support that selective targeting of SDHC by α-TOS derivatives 10 and 17 disrupts mitochondrial complex II function and redox homeostasis, thereby inducing apoptosis in SEM-type gastric cancer both in vitro and in vivo.

KRAS plays a crucial role in regulating cell survival and proliferation and is one of the most commonly mutated oncogenes in human cancers. The novel KRASG12D inhibitor, MRTX1133, demonstrates promising antitumor efficacy in vitro and in vivo. However, the development of acquired resistance in treated patients presents a considerable challenge to sustained therapeutic effectiveness. In response to this challenge, we conducted site-specific mutagenesis screening to identify potential secondary mutations that could induce resistance to MRTX1133. We screened a range of KRASG12D variants harboring potential secondary mutations, and 44 representative variants were selected for in-depth validation of the pooled screening outcomes. We identified eight variants (G12D with V9E, V9W, V9Q, G13P, T58Y, R68G, Y96W, and Q99L) that exhibited substantial resistance, with V9W showing notable resistance, and downstream signaling analyses and structural modeling were conducted. We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.

The authors would like to make a correction to the previous article [...]

BackgroundSince NEK7 is critical for NLRP3 inflammasome activation, NEK7 inhibitors could be employed as therapeutic agents against gout, a representative disease caused by NLRP3 inflammasome.MethodsWe designed NEK7 inhibitors based on biochemical kinome profiling of 2,7-substituted thieno[3,2-d]pyrimidine derivatives (SLC3031~3035 and SLC3037). Inflammasome activation was assessed by ELISA of IL-1b and immunoblotting of IL-1b maturation after treatment of bone marrow-derived macrophages with LPS+monosodium urate (MSU). NLPR3 binding to NEK7 and oligomerization were examined using immunoprecipitation and Blue Native gel electrophoresis, respectively. In vivo effect was investigated by studying gross and histopathological changes of food pad tissue of MSU-injected mice, together with assays of maturation of IL-1b and ASC speck in the tissue.ResultsSLC3037 inhibited inflammasome by MSU and other inflammasome activators through blockade of NLRP3 binding to NEK7 or oligomerization, and subsequent ASC oligomerization/phosphorylation. SLC3037 significantly reduced foot pad thickness and inflammation by MSU, which was superior to the effects of colchicine. SLC3037 significantly reduced content or maturation of IL-1b and ASC speck in the food pad. The number and height of intestinal villi were decreased by colchicine but not by SLC3037.ConclusionSLC3037, a NLRP3 inhibitor blocking NEK7 binding to NLRP3, could be a novel agent against diseases associated with NLRP3 inflammasome activation such as gout, cardiovascular diseases, metabolic syndrome or neurodegenerative diseases.

KRAS plays a crucial role in regulating cell survival and proliferation and is one of the most commonly mutated oncogenes in human cancers. The novel KRASG12D inhibitor, MRTX1133, demonstrates promising antitumor efficacy in vitro and in vivo. However, the development of acquired resistance in treated patients presents a considerable challenge to sustained therapeutic effectiveness. In response to this challenge, we conducted site-specific mutagenesis screening to identify potential secondary mutations that could induce resistance to MRTX1133. We screened a range of KRASG12D variants harboring potential secondary mutations, and 44 representative variants were selected for in-depth validation of the pooled screening outcomes. We identified eight variants (G12D with V9E, V9W, V9Q, G13P, T58Y, R68G, Y96W, and Q99L) that exhibited substantial resistance, with V9W showing notable resistance, and downstream signaling analyses and structural modeling were conducted. We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its m6A methyl transferase activity. We have explored PROTACs targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes degradation of METTL3 with a DC50 value of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 is capable of reversing differentiation and possesses anti-proliferative effects surpassing the small molecule inhibitors on MOLM-13 cells. Notably, we first present that METTL3 degrader significantly suppresses the growth of various gastric cancer (GC) cells, where the m6A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effects of KH12 were further confirmed in patient-derived organoids (PDOs). This study offers therapeutic potentials of targeted degradation of METTL3 against GC implicated with noncatalytic function of METTL3 as well as against AML.

Abstract Background: PHI-501 is a newly developed, highly effective, and orally accessible dual inhibitor for pan-RAF and discoidin domain receptor (DDR) that is a collagen-activated receptor tyrosine kinase. Mutations of the BRAF and NRAS are the most common genetic alterations in melanoma and consequently lead to activation of mitogen activated protein kinase (MAPK) signaling. The major drawback of melanoma treatment is the innate and acquired drug resistance to MAPK inhibitors. In this study, we investigated the inhibitory effects of a novel compound, PHI-501 on resistance to known BRAF and MEK inhibitors in melanoma. Methods: After compounds treatment, the growth-inhibiting activity was assessed using the CCK test. Inhibition of RAF/DDR1 pathway signaling was evaluated by western blotting. Using annexin-V/propidium iodide-stained cells and flow cytometry, apoptosis induction was assessed. To quantify cell mobility, monolayer cells were subjected to a wound-healing assay. Long-term therapy with dabrafenib (BRAF inhibitor), cobimetinib or trametinib (MEK inhibitor) led to the establishment of the drug-resistant SK-MEL-3 (BRAF V600E) and SK-MEL-30 (NRAS Q61K) melanoma cell line. Results: PHI-501 demonstrated potent growth inhibition (GI50 <1 µM) in seven melanoma cell lines harboring BRAF V600E or NRAS mutations. Western blot revealed that PHI-501 inhibited the phosphorylation of MEK, ERK, and AKT proteins in the downstream signaling of RAF/DDRs and decreased the levels of cyclin D1 and survivin. In SK-MEL-3, PHI-501 was 47-fold more effective than the class I BRAF inhibitor, dabrafenib (GI50: 0.08 µM vs 3.73 µM). Established dabrafenib- or trametinib-resistant SK-MEL-3 cells were extremely sensitive to PHI-501 (GI50: 0.20 µM and 0.13 µM), whereas their sensitivity to dabrafenib or trametinib was diminished (GI50: NA and 39.61 µM). PHI-501 triggered apoptosis more effectively than these inhibitors, as revealed by a larger proportion of annexin staining and extensive PARP1 cleavage. Comparing the potency of PHI-501 to cobimetinib in acquired resistant SK-MEL-30 cells showed that PHI-501 had 74-fold more inhibitory effect on cell proliferation (GI50: 0.55 µM to 40 µM). Moreover, treatment with PHI-501 strongly suppressed cell migration of cobimetinib-resistant SK-MEL-30 cells. PHI-501 inhibited the growth of drug-resistant melanoma cells as effectively as the original drug-naïve cells, and western blot analysis revealed considerable suppression of DDR1/2, ERK, and AKT phosphorylation in MAPK inhibitor-resistant cells. Conclusion: Melanoma cells resistant to RAF or MEK-targeted treatments or harboring NRAS mutation exhibited strong antiproliferative activity when treated with PHI-501, a highly potent pan-RAF/DDR dual inhibitor. The results of this study suggest that PHI-501, as a single agent, has the potential to overcome the restricted response in the treatment of melanoma. Citation Format: Sue Min Kim, Jung Hee Park, Ky-Youb Nam, June H-J Han, Kyu-Tae Kim, Jeong Hyeok Yoon, Sandip Sengupta, Taebo Sim, Sang Joon Shin. PHI-501, a novel pan-RAF/DDRs dual kinase inhibitor, overcomes BRAF or MEK inhibitor resistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 411.