RAF1 Raf-1 proto-oncogene, serine/threonine kinase
ENSG00000132155 · protein coding · Open Targets profile
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal- regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation. {ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:16924233, ECO:0000269|PubMed:9360956}.
Each band is a group of drugs. It runs from the kind of drug on the left to the furthest stage that drug has reached in any disease on the right. Thicker bands mean more drugs.
Approved bands are highlighted. Withdrawn means the drug was pulled from the market or from development. A combined phase counts as the later one (Phase 1/2 is shown as Phase 2). Hover a band for the drug names. Source: Open Targets Platform, fetched live.
Each row is a cancer, strongest overall evidence first. The two dots show how strong the inherited (germline) and tumour-mutation (somatic) evidence is; the line between them is the gap.
Scores run from 0 (no evidence) to 1 (strongest). A missing dot at 0 means Open Targets holds no evidence of that kind. Source: Open Targets Platform, fetched live.
Tractability
- Small molecule
- Approved Drug, Structure with Ligand, High-Quality Ligand, High-Quality Pocket, Druggable Family
- Antibody
- GO CC high conf, UniProt loc med conf, Human Protein Atlas loc
- PROTAC
- Database Ubiquitination, Half-life Data, Small Molecule Binder
gnomAD loss of function constraint: o/e 0.3329100012779236 (upper bound 0.45910000801086426). Low values mean loss of function is poorly tolerated, a safety flag for inhibition.
Who runs trials of these drugs
Principal investigators and study chairs on 324 registry trials, updated in the last three years, of the most advanced drugs against RAF1 (sorafenib, tovorafenib, regorafenib, naporafenib, belvarafenib), ranked by Phase 2+ trials. Live from ClinicalTrials.gov.
- Kanwal RaghavM.D. Anderson Cancer Center · 3 of 3 trials Phase 2+Ph2NCT07071961 · Regorafenib (Reg) and Lorigerlimab (Lor), RELO Regimen, in Treatment of High-risk Patients With Colorectal Cancer With Radiographic Occult Molecular Residual Disease After End of Established Definitive Therapy [ReLOAD Trial]brief
- Nicolas PenelCentre Oscar Lambret · 3 of 3 trials Phase 2+
- Jean-Yves BLAYCentre Leon Berard · 2 of 3 trials Phase 2+Ph2NCT02029001 · Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatmentbrief
- Marwan G FakihCity of Hope Medical Center · 2 of 3 trials Phase 2+Ph1/Ph2NCT05672316 · Botensilimab, Balstilimab and Regorafenib for the Treatment of Patients With Microsatellite Stable Metastatic Colorectal Cancer Who Have Progressed on Prior Chemotherapybrief
- Emmanuelle SAMALINCRLC Val d'Aurelle-Paul Lamarque · 2 of 2 trials Phase 2+
- Eric ShermanMemorial Sloan Kettering Cancer Center · 2 of 2 trials Phase 2+
- Ghassan Abou-AlfaMemorial Sloan Kettering Cancer Center · 2 of 2 trials Phase 2+
- Lin ShenPeking University Cancer Hospital & Institute · 2 of 2 trials Phase 2+
- Maria ReigBCLC group. Liver Unit. Hospital Clinic. Ciberehd · 2 of 2 trials Phase 2+
- Sukeshi Patel AroraCancer Therapy & Research Center University of Texas Health Science Center San Antonio · 2 of 2 trials Phase 2+
- Ying YuanSecond Affiliated Hospital, Zhejiang University, School of Medicine · 2 of 2 trials Phase 2+
- Florence DUFFAUDLa Timone University Hospital · 1 of 2 trials Phase 2+
- Joyce AntalClinical Development · 1 of 2 trials Phase 2+
- Abdullah EsmailHouston Methodist Neal Cancer Center · 1 of 1 trials Phase 2+
- Aiping ZhouCancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College · 1 of 1 trials Phase 2+
Registry trials of sorafenib, tovorafenib, regorafenib, naporafenib, belvarafenib updated in the last three years, counted by the country group of their listed sites. A trial with sites in several groups counts in each; 227 of 299 have all sites in one country.
Site counts are not patients per country, and trials registered only outside ClinicalTrials.gov are not covered. Where sites are is a fact about the record, not a judgement of its quality. Europe is the EU and EEA, the UK and Switzerland. 25 trials list no sites and are left out. Source: ClinicalTrials.gov, fetched live.
202 trials of drugs against RAF1 were stopped early; 41 of the 200 most recent give no reason
Terminated, withdrawn and suspended interventional trials of sorafenib, tovorafenib, regorafenib, naporafenib, belvarafenib, XL-281, LY-3009120, ARQ-736, newest update first, live from ClinicalTrials.gov. Each reason is quoted exactly as the registry gives it; we do not sort reasons into safety, efficacy or business. Dates are the last registry update. Showing the 25 most recent of 202.
- terminated · 2026-11-03 · Peking University Cancer Hospital & Institute · regorafenib“The study was stopped early due to lack of efficacy.”
- suspended · 2026-10-20 · City of Hope Medical Center · Regorafenib“resources”
- terminated · 2026-10-05 · Children's Oncology Group · Regorafenib“Drug supply issues”
- terminated · 2026-08-26 · Bristol-Myers Squibb · RegorafenibNo reason given
- terminated · 2026-07-06 · Syndax Pharmaceuticals · matched by the registry's drug synonyms“Study was terminated by sponsor after Phase 1b as pre-defined signals of efficacy were not met in the Phase 1b dose expansion cohort.”
- withdrawn · 2026-06-15 · University of Miami · Regorafenib“Investigator decision”
- withdrawn · 2026-03-11 · M.D. Anderson Cancer Center · Regorafenib“0 participants enrolled”
- terminated · 2026-03-09 · Translational Research in Oncology · Regorafenib in combination with pembrolizumab“The trial ended earlier than planned due to slow enrolment, which has made it unfeasible to achieve the target sample size within a reasonable timeframe. Consequently, a business decision has been made to discontinue funding for the trial.”
- terminated · 2026-03-05 · Wake Forest University Health Sciences · Regorafenib“Slow accruals”
- withdrawn · 2026-02-25 · M.D. Anderson Cancer Center · Regorafenib“0 participants enrolled”
- terminated · 2026-01-20 · Anwaar Saeed · Regorafenib“Terminated per directive from Bayer due to funding.”
- terminated · 2025-12-24 · Novartis Pharmaceuticals · matched by the registry's drug synonyms“The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations.”
- suspended · 2025-10-23 · Mirror Biologics, Inc. · Sorafenib“Sponsor unable to fund”
- terminated · 2025-10-02 · Day One Biopharmaceuticals, Inc. · Tovorafenib“Sponsor decision”
- terminated · 2025-08-14 · Day One Biopharmaceuticals, Inc. · Tovorafenib, Tovorafenib Drug: Pimasertib“Sponsor decision”
- withdrawn · 2025-08-06 · M.D. Anderson Cancer Center · Sorafenib“0 participants”
- withdrawn · 2025-04-27 · Medical University of South Carolina · matched by the registry's drug synonyms“study is being rewritten for different disease population”
- terminated · 2025-04-13 · Novartis Pharmaceuticals · matched by the registry's drug synonyms“Business reasons”
- terminated · 2025-03-30 · UNICANCER · Regorafenib then Trifluridine/Tipiracil, Trifluridine/Tipiracil then Regorafenib“Following the presentation of the SUNLIGHT study results at ASCO GI and the rapid change in patient management in the majority of centers, the IDMC experts recommended halting inclusion in the SOREGATT study with immediate effect.”
- terminated · 2025-03-11 · Great Novel Therapeutics Biotech & Medicals Corporation · Regorafenib“The overall profile does not support development for Hepatocellular Carcinoma”
- terminated · 2025-02-26 · Cancer Institute and Hospital, Chinese Academy of Medical Sciences · Sorafenib“IDMC recommended to terminate the study since Interim analysis showed that the experimental group had significant superiority over the control group in TTP and OS (p<0.001), meeting the predefined interim analysis endpoints in the study protocol.”
- terminated · 2025-02-12 · Georgetown University · matched by the registry's drug synonyms“Lack of efficacy”
- terminated · 2024-12-11 · ImmunityBio, Inc. · Regorafenib“low enrollment”
- withdrawn · 2024-11-21 · City of Hope Medical Center · Regorafenib“Abandoned 9/23/24”
- terminated · 2024-11-20 · Astellas Pharma Inc · matched by the registry's drug synonyms“Company decided not to pursue the development of this drug in this patient population at this time”
Paediatric incentives and obligations for RAF1's drugs
For sorafenib, tovorafenib, regorafenib, naporafenib, belvarafenib, XL-281, LY-3009120, ARQ-736: what EMA and FDA publish about paediatric plans, orphan status and pediatric approvals, and how many registered studies take children. Each line is a yes, no or not published fact from the record linked under it; none of it is a forecast.
- FDA pediatric target list: no · RAF1 is not on the listRule: Target is on FDA's Pediatric Molecular Target List (relevant targets). Source: FDA Pediatric Molecular Target List (Listed as February 2026 on the FDA Pediatric Oncology page; the file served is 9.7.22_the_relevant_molecular_target_list.xlsx, whose Summary of Changes sheet is headed 'SEPTEMBER 2022 UPDATE' (footnote date 2022-09-01)), 2026-11-11
- EU paediatric investigation plan: yes · EMA/PE/0000182170 (regorafenib, Treatment of all conditions contained in the category of malignant neoplasms (except haematopoietic and lymphoid tissue)): PM: decision on the application for modification of an agreed PIP, 5 Dec 2024; EMEA-002763-PIP01-20-M01 (tovorafenib, Treatment of paediatric low grade glioma): PM: decision on the application for modification of an agreed PIP, 27 Oct 2023; EMEA-000781-PIP01-09 (sorafenib tosilate, Differentiated thyroid cancer): W: decision granting a waiver in all age groups for all conditions or indications, 4 May 2010Rule: An EMA PIP decision (agreement, modification or waiver) lists the drug as its active substance, exact name. Source: EMA data download (dated snapshot), 2026-11-11
- EU orphan designation: yes · EU/3/21/2434 positive 20 May 2021: Treatment of glioma; EU/3/13/1200 expired 13 Nov 2013: Treatment of papillary thyroid cancer; EU/3/13/1199 expired 13 Nov 2013: Treatment of follicular thyroid cancer; EU/3/19/2177 withdrawn 28 Jun 2019: Treatment of glioma; +3 moreRule: An EU orphan designation lists the drug as its active substance (exact name) or belongs to a medicine that does; withdrawn and expired designations are listed with their status. Source: EMA data download (dated snapshot), 2026-11-11
- Authorised in the EU: yes · Ojemda: authorised since 20 Apr 2026, orphan medicine, conditional; Sorafenib Accord: authorised since 9 Nov 2022; Stivarga: authorised since 26 Aug 2013; Nexavar: authorised since 19 Jul 2006Rule: An EMA medicine record lists the drug as its active substance or INN, exact name; national-only authorisations are not in this file. Source: EMA data download (dated snapshot), 2026-11-11
- FDA orphan designation: not published · FDA's orphan designation database turns away automated requests, so this app does not read it; search it by hand at the linkRule: Would be: an FDA orphan designation names the drug. Source: FDA orphan designations search
- FDA pediatric oncology approval: yes · Tovorafenib [Ojemda], 23 Apr 2024: Treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutationRule: FDA's Pediatric Oncology Drug Approvals table names the drug. Source: FDA Pediatric Oncology Drug Approvals (content current as of 2026-03-03), 2026-11-12
- Registered studies open to children: yes · 84 interventional studies of sorafenib, tovorafenib, regorafenib, naporafenib, belvarafenib, xl-281, ly-3009120, arq-736 include patients under 18; 31 are recruiting, not yet recruiting or activeRule: The registry's age group includes Child (birth to 17 years), which also counts studies that set no minimum age. Source: ClinicalTrials.gov search, 2026-11-12
Rare pediatric disease voucher. FDA, content current as of 29 Apr 2026: “As of February 3, 2026, enactment of the Consolidated Appropriations Act, 2026, the rare pediatric disease PRV program will sunset after September 30, 2029. FDA may not award any PRVs under this program after September 30, 2029.” Voucher sale prices are not shown here; they appear only as company-reported news. FDA: Rare Pediatric Disease Designation and Priority Review Voucher Programs
All 9 drugs and clinical candidates as a table
Each drug, stage and indication links to its Open Targets record, where the trials and approvals behind it are listed. Salt forms (for example a mesylate) are listed as Open Targets records them, as separate entries.