EGFR C797S inhibitors(Epidermal Growth Factor Receptor C797S inhibitors), EGFR T790M inhibitors(EGFR T790M inhibitors), EGFR exon 19 deletion inhibitors

+ [1]

Therapeutic Areas

NeoplasmsRespiratory Diseases

Active Indication-

Inactive Indication

AdenocarcinomaBronchogenic CarcinomaEGFR positive non-small cell lung cancer+ [5]

Originator Organization

Blueprint Medicines Corp.

Active Organization-

Inactive Organization

Blueprint Medicines Corp.

Zai Lab (Shanghai) Co., Ltd.Patheon Development Services, Inc.

Drug Highest PhaseSuspendedPhase 2

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC28H37FN6O3S

InChIKeyLIMFPAAAIVQRRD-BCGVJQADSA-N

CAS Registry2660250-10-0

Clinical Trials associated with Tigozertinib

CTR20221771

/ SuspendedPhase 1/2

一项治疗EGFR突变型非小细胞肺癌获得性耐药的I/II期研究

[Translation] A phase I/II study for the treatment of acquired drug resistance in EGFR-mutant non-small cell lung cancer

在携带有EGFR突变的NSCLC患者中评估在RP2D下BLU-945单药治疗的抗肿瘤活性等

[Translation]

Evaluate the antitumor activity of BLU-945 monotherapy at RP2D in NSCLC patients with EGFR mutations, etc.

Start Date-

Sponsor / Collaborator

Zai Lab (Shanghai) Co., Ltd.

[+2]

NCT04862780

/ TerminatedPhase 1

A Phase 1/2 Study Targeting Acquired Resistance Mechanisms in Patients With EGFR Mutant Non-Small Cell Lung Cancer

This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of BLU-945, a selective EGFR inhibitor, as monotherapy or in combination with osimertinib.

Start Date29 Jun 2021

Sponsor / Collaborator

Blueprint Medicines Corp.

100 Clinical Results associated with Tigozertinib

100 Translational Medicine associated with Tigozertinib

100 Patents (Medical) associated with Tigozertinib

Literatures (Medical) associated with Tigozertinib

01 Apr 2025·International Journal of Biological Macromolecules

Identification of novel inhibitors for epidermal growth factor receptor tyrosine kinase using absolute binding free-energy simulations

Article

Author: Fu, Haohao ; Cai, Wensheng ; Shao, Xueguang ; Zhou, Huaxin

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR), a critical biological macromolecule involved in cell growth and division, can lead to drug resistance in patients undergoing chemotherapy with kinase inhibitors. Notably, the emergence of the C797S mutation poses new challenges for targeted EGFR therapy, highlighting the urgent need for agents effective against this triple mutation (L858R/T790M/C797S, EGFR™). Building on our previous finding that sulfonyl and piperidinyl groups significantly contribute to the EGFR™-inhibitor interactions, we have identified the best-in-class inhibitors containing these groups through functional-group-based screening and formally exact absolute binding free-energy calculations. Our new strategy offers greater flexibility than traditional workflows leaning on relative binding free-energy calculations and accommodates ligands with substantial structural variations. The result shows that the top candidate exhibits a binding affinity of -15.8 kcal/mol towards the EGFR™ mutant, surpassing BLU-945, a state-of-the-art fourth-generation inhibitor with a binding free energy of -12.6 kcal/mol. Subsequent free-energy decomposition indicates that the presented top candidate primarily enhances interactions with the K745, D800 and R841 residues, suggesting its potential to overcome resistance from the C797S mutation. Notably, K745 forms highly favorable hydrogen bonds and cation-π interactions with C6. Targeting lysine has emerged as a promising strategy, especially in cases where the C797S mutation renders traditional covalent inhibitors ineffective. We propose that these novel inhibitors represent promising drug candidates for non-small cell lung cancer treatment and offer new strategies to overcome drug resistance caused by EGFR mutation.

03 Mar 2024·Journal of Biomolecular Structure and Dynamics

Computational investigation of Moringa oleifera phytochemicals targeting EGFR: molecular docking, molecular dynamics simulation and density functional theory studies

Article

Author: Anwer, Sadia Anjum ; Basheera, Shefin ; Yousaf, Muhammad Abrar ; Sivanandan, Sreekumar

Epidermal growth factor receptor (EGFR) is a prominent target for anticancer therapy due to its role in activating several cell signaling cascades. Clinically approved EGFR inhibitors are reported to show treatment resistance and toxicity, this study, therefore, investigates Moringa oleifera phytochemicals to find potent and safe anti-EGFR compounds. For that, phytochemicals were screened based on drug-likeness and molecular docking analysis followed by molecular dynamics simulation, density functional theory analysis and ADMET analysis to identify the effective inhibitors of EGFR tyrosine kinase (EGFR-TK) domain. Known EGFR-TK inhibitors (1-4 generations) were used as control. Among 146 phytochemicals, 136 compounds showed drug-likeness, of which Delta 7-Avenasterol was the most potential EGFR-TK inhibitor with a binding energy of -9.2 kcal/mol followed by 24-Methylenecholesterol (-9.1 kcal/mol), Campesterol (-9.0 kcal/mol) and Ellagic acid (-9.0 kcal/mol). In comparison, the highest binding affinity from control drugs was displayed by Rociletinib (-9.0 kcal/mol). The molecular dynamics simulation (100 ns) exhibited the structural stability of native EGFR-TK and protein-inhibitor complexes. Further, MM/PBSA computed the binding free energies of protein complex with Delta 7-Avenasterol, 24-Methylenecholesterol, Campesterol and Ellagic acid as -154.559 ± 18.591 kJ/mol, -139.176 ± 19.236 kJ/mol, -136.212 ± 17.598 kJ/mol and -139.513 ± 23.832 kJ/mol, respectively. Non-polar interactions were the major contributors to these energies. The density functional theory analysis also established the stability of these inhibitor compounds. ADMET analysis depicted acceptable outcomes for all top phytochemicals without displaying any toxicity. In conclusion, this report has identified promising EGFR-TK inhibitors to treat several cancers that can be further investigated through laboratory and clinical tests.

01 Feb 2024·Molecular Pharmacology

A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology

Article

Author: Beyett, Tyler S ; Eck, Michael J ; Heppner, David E ; Jänne, Pasi A ; To, Ciric ; Schaeffner, Ilse K ; Kim, Justin J

Lung cancer is commonly caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric kinase inhibitors are unaffected by common ATP-site resistance mutations and represent a promising therapeutic strategy for targeting drug-resistant EGFR variants. However, allosteric inhibitors are antagonized by kinase dimerization, and understanding this phenomenon has been limited to cellular experiments. To facilitate the study of allosteric inhibitor pharmacology, we designed and purified a constitutive EGFR kinase dimer harboring the clinically relevant L858R/T790M mutations. Kinetic characterization revealed that the EGFR kinase dimer is more active than monomeric EGFR(L858R/T790M) kinase and has the same K_m,ATP Biochemical profiling of a large panel of ATP-competitive and allosteric EGFR inhibitors showed that allosteric inhibitor potency decreased by >500-fold in the kinase dimer compared with monomer, yielding IC₅₀ values that correlate well with Ba/F3 cellular potencies. Thus, this readily purifiable constitutive asymmetric EGFR kinase dimer represents an attractive tool for biochemical evaluation of EGFR inhibitor pharmacology, in particular for allosteric inhibitors. SIGNIFICANCE STATEMENT: Drugs targeting epidermal growth factor receptor (EGFR) kinase are commonly used to treat lung cancers but are affected by receptor dimerization. Here, we describe a locked kinase dimer that can be used to study EGFR inhibitor pharmacology.

News (Medical) associated with Tigozertinib

09 Jan 2024

·www.fiercebiotech.com

JPM24, Day 2: GSK, Eli Lilly, Blueprint, SR One and more

Merger Monday lived up to its name, but Day 2 is also seeing deals at JPM 24. Welcome to Day 2 of the J.P. Morgan Healthcare Conference 2024 in San Francisco. Yesterday "Merger Monday" lived up to its name with deals for Novartis, J&J and Merck, and today, we’re also starting Tuesday with an early deal. Check out that deal and all the updates from JPM below. Want more? Fierce Biotech’s conference's kickoff Day 1 is available here, and Fierce Pharma’s can be found here. Tuesday 6:43 p.m. ET Jan. 9 Eli Lilly CEO David Ricks, speaking to the slow and steady progress that brought tirzepitide to the world, says the Indianapolis pharma is now ready to open up the chocolate factory. “I know a number of biotechs are in the room at this conference so it's worth mentioning: we're open for business on external innovation,” Ricks said at the J.P. Morgan Healthcare Conference Tuesday. Story Tuesday 6:10 p.m. ET Jan. 9 SR One CEO and managing partner Simeon George, M.D., said the firm was eyeing some investments in psychedelic-focused biotechs but is waiting on formally financing one to see how the space matures. He specifically pointed to the rollout of J&J's Spravato, an esketamine spray used to treat major depression. The treatment is currently one of J&J's fastest-growing products and is a pillar in the company's neuroscience portfolio. "We've been watching, obviously, how that has gone in terms of the launch and again, that product looks like it's starting to be on a nice ramp there," George said in an interview with Fierce Biotech on Tuesday. "My sense is there's going to be more than a couple of companies that will be interesting to look at from a fundraising perspective." George said there are probably "one or two" companies on the firm's shortlist, though he wouldn't specify which. Tuesday 3:45 p.m. ET Jan. 9 "We're seeing companies make investments in traditional pharma assets that are a little further along in the development pipeline," Sharon Flanagan, managing partner for global law firm Sidley's San Francisco office, told Fierce Biotech on the conference sidelines. "ADCs (antibody drug conjugates) are really interesting," she continued, citing Johnson & Johnson's $2 billion acquisition of ADC-focused Ambrx Biopharma. "So that's a way to do something that's still pharma, but with something novel and interesting, that has a spin to it. I do think in markets that are a little uncertain, sometimes the more truly novel types of products might get less interest." Tuesday 9:45 a.m. ET Jan. 9 Blueprint Medicines is pulling back from a core focus area, cutting two non-small lung cancer programs after getting a peak of early data. It was just a year ago that CEO Kate Haviland touted the EGFR tyrosine kinase inhibitors as the company's path to first-line treatment. The biotech says it will explore possible out-licensing deals to find a home for BLU-945 and BLU-451. Story Tuesday 3 a.m. ET Jan. 9 GSK is getting in on the M&A action as it snaps up respiratory biotech Aiolos Bio for $1 billion upfront and $400 million in biobucks. The deal sees GSK nab Aiolos’ leading asset AIO-001, a phase 2-ready mAb, with plans for the drug to also treat chronic rhinosinusitis with nasal polyps. Story.

09 Jan 2024

·www.fiercebiotech.com

Blueprint tears up plans, dropping 2 lung cancer programs after seeing early clinical data

Blueprint disclosed the news alongside an update on its plans for Gavreto. Blueprint Medicines is pulling back from one of its three areas of focus, dropping two non-small cell lung cancer (NSCLC) programs in response to early clinical data on the EGFR tyrosine kinase inhibitors. One year ago, Blueprint CEO Kate Haviland used a presentation at the J.P. Morgan Healthcare Conference to explain how the company designed a phase 1 EGFR-driven lung cancer study to give “the confidence that we can win in first line.” The decision to spend 2023 gathering data to inform a go/no-go decision reflected Haviland’s recognition that lung cancer was an ambitious and potentially “expensive endeavor.” Now, Blueprint has early evidence of whether its two drug candidates, BLU-945 and BLU-451, can deliver on its aim to develop best-in-class molecules capable of replacing the standard of care in frontline, EGFR lung cancer. Haviland pulled investment in the programs after getting a look at the data. “Combining this emerging data, from both the BLU-945 and the BLU-451 programs, with the evolving EGFR landscape, we have decided to deprioritize continued investment in EGFR-driven non-small cell lung cancer and to focus our R&D investments in the most compelling and highest value programs,” the CEO said at a JPM presentation this week. Blueprint’s interest in EGFR-driven lung cancer was built on evidence that the first three generations of TKIs had failed to address the need for a molecule that maintains activity against sensitizing mutations, notably L858R. The L858R mutation is associated with worse outcomes on the current standard of care. Blueprint believed a combination with AstraZeneca’s Tagrisso could provide more durable benefits. While the biotech has opted against spending its own cash to pursue that belief, it will “explore strategic options, including potential out-licensing” to support further development of BLU-945 and BLU-451. Blueprint disclosed the news alongside an update on its plans for Gavreto, the approved RET inhibitor that Roche decided to drop 11 months ago. Lacking global infrastructure in lung and thyroid cancer, the approved indications for Gavreto, Blueprint is stopping global development and marketing of the drug outside of the U.S. and China. CStone Pharmaceuticals owns the rights to Gavreto in China. In the U.S., Blueprint has found “a potential alternate partner” and “is continuing to work with the involved parties to define a scenario that enables continued availability of Gavreto.” Winding down work on Gavreto outside of those markets will reduce operating expenses without affecting the $175 million Blueprint received from Royalty Pharma in 2022.

Phase 1License out/inDrug Approval

09 Jan 2024

·firstwordpharma.com

Blueprint guts lung cancer portfolio, pulling Gavreto in certain markets

Blueprint Medicines is deprioritising some lung cancer programmes, citing an "evolving external landscape, emerging clinical data and partnering considerations." In an update at the ongoing JP Morgan healthcare conference, Blueprint said it would be scaling back Gavreto (pralsetinib) in certain markets, and culling a pair of early-stage assets.Last year, Roche terminated a collaboration between the companies due to strategic considerations and handed back global commercialisation and development rights for Gavreto, which is approved in the US to treat RET fusion-positive populations of non-small-cell lung cancer (NSCLC) and thyroid cancer. Gavreto had also received FDA accelerated approval for RET-mutant medullary thyroid cancer, but the partners withdrew the oral RET inhibitor for the indication last summer.Another partner to the rescue?Citing a lack of global infrastructure in lung and thyroid cancer, Blueprint now says it has decided to discontinue global development and marketing of Gavreto in territories excluding the US and China. It expects to begin winding down activities in the first quarter of 2024. An alternate partner for Gavreto in the US may be waiting in the wings, however; Blueprint said it is working with the parties involved to define a scenario that would allow the drug to continue to be available in the country.The move won't affect the $175-million upfront payment Blueprint received under a 2022 financing agreement with Royalty Pharma.Meanwhile, Blueprint also hinted that "emerging clinical data" spurred a decision to discontinue investing in the early-stage therapies BLU-945 and BLU-451 for EGFR-mutant NSCLC. The company got hold of BLU-451 via its purchase of Lengo Therapeutics in 2021 for up to $465 million, elbowing its way into an increasingly crowded niche within lung cancer.It is now considering different options for the assets, including potential out-licensing. That leaves BLU-525, another EGFR inhibitor, as Blueprint's sole pipeline candidate for lung cancer, according to its website.

AcquisitionAccelerated ApprovalDrug ApprovalLicense out/in

100 Deals associated with Tigozertinib

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
EGFR positive non-small cell lung cancer	Phase 2	New Zealand	Blueprint Medicines Corp.	04 Apr 2023
EGFR positive non-small cell lung cancer	Phase 2	Spain	Zai Lab (Shanghai) Co., Ltd.	04 Apr 2023
EGFR positive non-small cell lung cancer	Phase 2	New Zealand	Blueprint Medicines Corp.	04 Apr 2023
EGFR positive non-small cell lung cancer	Phase 2	Spain	Zai Lab (Shanghai) Co., Ltd.	04 Apr 2023
Adenocarcinoma	Phase 2	United States	Blueprint Medicines Corp.	21 Apr 2021
Bronchogenic Carcinoma	Phase 2	United States	Blueprint Medicines Corp.	21 Apr 2021
Lung Cancer	Phase 2	United States	Blueprint Medicines Corp.	21 Apr 2021
Nerve Tissue Neoplasms	Phase 2	United States	Blueprint Medicines Corp.	21 Apr 2021
Non-Small Cell Lung Cancer	Phase 2	United States	Blueprint Medicines Corp.	21 Apr 2021
Respiratory Tract Neoplasms	Phase 2	United States	Blueprint Medicines Corp.	21 Apr 2021

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04862780 (SYMPHONY, ASCO 12023 \| ASCO 22023) Manual	Phase 1/2	Non-Small Cell Lung Cancer EGFR Mutation	133	BLU-945	(fjnaplnrrp) = BLU-945 mono group: nausea (42%), headache (40%), increased ALT (38%), increased AST (37%), and vomiting (32%); BLU-945+OSI group: fatigue (36%), diarrhea (32%), headache (32%), and nausea (28%) yrasfbosrh (tayxkiqfpc ) View more	Positive	26 May 2023
				BLU-945+Osimertinib

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