Lifirafenib
(Synonyms: BGB-283) 目录号 : GC60992Lifirafenib (BGB-283, Beigene-283) potently inhibits RAF family kinases and EGFR activities in biochemical assays with IC50 values of 23, 29 and 495 nM for the recombinant BRAFV600E kinase domain, EGFR and EGFR T790M/L858R mutant.
Cas No.:1446090-79-4
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Lifirafenib (BGB-283, Beigene-283) potently inhibits RAF family kinases and EGFR activities in biochemical assays with IC50 values of 23, 29 and 495 nM for the recombinant BRAFV600E kinase domain, EGFR and EGFR T790M/L858R mutant.
In vitro, BGB-283 potently inhibits BRAFV600E-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAFV600E and EGFR mutation/amplification. In BRAFV600E colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. It demonstrates selective cytotoxicity to cell lines harboring BRAFV600E or EGFR mutations. BGB-283 inhibits the EGF-induced EGFR autophosphorylation on Tyr1068 in A431 cells in a dose-dependent manner. In WiDr colorectal cancer cells, BGB-283 is shown to be able to inhibit the feedback activation of EGFR signaling and achieves sustained inhibition of pERK[1].
In vivo, BGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAFV600E mutation. BGB-283 is highly efficacious in BRAF(V600E) colorectal cancer xenograft models, including HT29, Colo205, and two primary tumor xenografts harboring BRAFV600E mutation. In addition, BGB-283 shows compelling efficacy in a WiDr xenograft model where EGFR reactivation is shown to be induced upon BRAF inhibition. BGB-283 induces tumor regression in HCC827 but not in A431 xenograft. BGB-283 inhibits phosphorylation of both ERK1/2 and EGFR and displays potent antitumor activity in WiDr tumor xenografts. BGB-283 does not induce EGFR feedback activation as reported for vemurafenib. BGB-283 potently inhibits MEK and ERK phosphorylation and DUSP6 expression in vivo when dosed repeatedly. There is no detectable difference on AKT phosphorylation[1].
[1] Tang Z, et al. Mol Cancer Ther. 2015, 14(10):2187-97.
Cas No. | 1446090-79-4 | SDF | |
别名 | BGB-283 | ||
Canonical SMILES | O=C1NC2=NC=CC(OC3=CC=C(O[C@@]4([H])[C@]5([H])[C@@H]4C6=NC7=CC=C(C(F)(F)F)C=C7N6)C5=C3)=C2CC1 | ||
分子式 | C25H17F3N4O3 | 分子量 | 478.42 |
溶解度 | DMSO: ≥ 100 mg/mL (209.02 mM) | 储存条件 | Store at -20°C |
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Targeting oncogenic Raf protein-serine/threonine kinases in human cancers
Pharmacol Res 2018 Sep;135:239-258.PMID:30118796DOI:10.1016/j.phrs.2018.08.013.
The Ras-Raf-MEK-ERK signal transduction cascade is arguably the most important oncogenic pathway in human cancers. Ras-GTP promotes the formation of active homodimers or heterodimers of A-Raf, B-Raf, and C-Raf by an intricate process. These enzymes are protein-serine/threonine kinases that catalyze the phosphorylation and activation of MEK1 and MEK2 which, in turn, catalyze the phosphorylation and activation of ERK1 and ERK2. The latter catalyze the regulatory phosphorylation of dozens of cytosolic and nuclear proteins. The X-ray crystal structure of B-Raf-MEK1 depicts a face-to-face dimer with interacting activation segments; B-Raf is in an active conformation and MEK1 is in an inactive conformation. Besides the four traditional components in the Ras-Raf-MEK-ERK signaling module, scaffolding proteins such as Kinase Suppressor of Ras (KSR1/2) play an important role in this signaling cascade by functioning as a scaffold protein. RAS mutations occur in about 30% of all human cancers. Moreover, BRAFV600E mutations occur in about 8% of all cancers making this the most prevalent oncogenic protein kinase. Vemurafenib and dabrafenib are B-RafV600E inhibitors that were approved for the treatment of melanomas bearing the V600E mutation. Coupling MEK1/2 inhibitors with B-Raf inhibitors is more effective in treating such melanomas and dual therapy is now the standard of care. Vemurafenib and cobimetanib, dabrafenib and trametinib, and encorafenib plus binimetinib are the FDA-approved combinations for the treatment of BRAFV600E melanomas. Although such mutations occur in other neoplasms including thyroid, colorectal, and non-small cell lung cancers, these agents are not as effective in treating these non-melanoma neoplasms. Vemurafenib and dabrafenib produce the paradoxical activation of the MAP kinase pathway in wild type BRAF cells. The precise mechanism for this activation is unclear, but drug-induced Raf activating side-to-side dimerization appears to be an essential step. Although 63%-76% of all people with advanced melanoma with the BRAF V600E mutation derive clinical benefit from combination therapy, median progression-free survival lasts only about nine months and 90% of patients develop resistance within one year. The various secondary resistance mechanisms include NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-MAP kinase pathway alterations (11%). Vemurafenib and dabrafenib bind to an inactive form of B-Raf (αC-helixout and DFG-Din) and are classified as type I½ inhibitors. LY3009120 and Lifirafenib, which are in the early drug-development stage, bind to a different inactive form of B-Raf (DFG-Dout) and are classified as type II inhibitors. Besides targeting B-Raf and MEK protein kinases, immunotherapies that include ipilimumab, pembrolizumab, and nivolumab have been FDA-approved for the treatment of melanomas. Current clinical trials are underway to determine the optimal usage of targeted and immunotherapies.
Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations
J Thorac Oncol 2020 Oct;15(10):1611-1623.PMID:32540409DOI:10.1016/j.jtho.2020.05.021.
Introduction: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents. Methods: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines. Results: A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and Lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line. Conclusions: In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.
Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors
J Clin Oncol 2020 Jul 1;38(19):2140-2150.PMID:32182156DOI:10.1200/JCO.19.02654.
Purpose: Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of Lifirafenib in patients with B-RAF- or K-RAS/N-RAS-mutated solid tumors. Methods: During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of Lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. Results: The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF-mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF-mutated non-small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS-mutated endometrial cancer and K-RAS codon 12-mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS-mutated colorectal cancer (n = 20). Conclusion: Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600-mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS-mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of Lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.
Pathway-Centric Structure-Based Multi-Target Compound Screening for Anti-Virulence Drug Repurposing
Int J Mol Sci 2019 Jul 17;20(14):3504.PMID:31319464DOI:10.3390/ijms20143504.
The emergence of superbugs that are resistant to last-resort antibiotics poses a serious threat to human health, and we are in a "race against time to develop new antibiotics." New approaches are urgently needed to control drug-resistant pathogens, and to reduce the emergence of new drug-resistant microbes. Targeting bacterial virulence has emerged as an important strategy for combating drug-resistant pathogens. It has been shown that pyocyanin, which is produced by the phenazine biosynthesis pathway, plays a key role in the virulence of Pseudomonas aeruginosa infection, making it an attractive target for anti-infective drug discovery. In order to discover efficient therapeutics that inhibit the phenazine biosynthesis in a timely fashion, we screen 2004 clinical and pre-clinical drugs to target multiple enzymes in the phenazine biosynthesis pathway, using a novel procedure of protein-ligand docking. Our detailed analysis suggests that kinase inhibitors, notably Lifirafenib, are promising lead compounds for inhibiting aroQ, phzG, and phzS enzymes that are involved in the phenazine biosynthesis, and merit further experimental validations. In principle, inhibiting multiple targets in a pathway will be more effective and have less chance of the emergence of drug resistance than targeting a single protein. Our multi-target structure-based drug design strategy can be applied to other pathways, as well as provide a systematic approach to polypharmacological drug repositioning.
RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors
Mol Oncol 2020 Aug;14(8):1833-1849.PMID:32336014DOI:10.1002/1878-0261.12698.
The mutation of K-RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K-RAS mutations. The reduced sensitivity of K-RAS-mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C-RAF and with the reactivation of mitogen-activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors Lifirafenib (BGB-283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD-0325901) and selumetinib, in suppressing the proliferation of K-RAS-mutated non-small-cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B-RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF-dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K-RAS-mutated cells. This synergistic effect was also observed in several K-RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho-ERK blockade in enhancing the antitumor activity observed in the K-RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K-RAS-mutated cancers, and have led to a Phase 1b/2 combination therapy study of Lifirafenib and mirdametinib in solid tumor patients with K-RAS mutations and other MAPK pathway aberrations.