KRAS G12C inhibitors(GTPase KRas G12C inhibitors), KRAS G12D inhibitors(GTPase KRas G12D inhibitors), KRAS G12V inhibitors(GTPase KRas G12V inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

NeoplasmsKRAS mutation-related tumors

Inactive Indication-

Originator Organization

Memorial Sloan Kettering Cancer Center

Active Organization

Memorial Sloan Kettering Cancer Center

Boehringer Ingelheim GmbH

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC23H27N7O2S

InChIKeyMIUFORKWYHBPRW-HMFCALDFSA-N

CAS Registry2937327-93-8

100 Clinical Results associated with BI-2865

100 Translational Medicine associated with BI-2865

100 Patents (Medical) associated with BI-2865

Literatures (Medical) associated with BI-2865

01 Jun 2024·Cancer Letters

Site-specific mutagenesis screening in KRAS mutant library to uncover resistance mechanisms to KRASG12D inhibitors

Article

Author: Kim, Hui Kwon ; Choi, Jeesoo ; Kim, Kiwook ; Kim, Taeyul K ; Kim, Han Sang ; Park, Juyeong ; Sim, Taebo ; Jeon, Eunhye ; Kim, Jiyun ; Shin, Ju-Young ; Kim, Kyung-A ; Han, Yoon Dae

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 KRAS^G12D 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 KRAS^G12D 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 KRAS^G12D 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 KRAS^G12D-mutant cancers.

Cell Communication and Signaling

BI-2865, a pan-KRAS inhibitor, reverses the P-glycoprotein induced multidrug resistance in vitro and in vivo

Article

Author: Luo, Kewang ; Yang, Chuan ; Fu, Liwu ; Wang, Fang ; Fu, Kai ; Zhu, Shuangli ; Yang, Qihong ; To, Kenneth Kin Wah ; Pan, Can ; Hu, Guilin

AbstractBackgroundMultidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored.MethodsThe cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts’ tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate’s efflux were analyzed through the vanadate-sensitive ATPase assay, [125I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence.ResultsWe found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What’s more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity.ConclusionsThis study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers.

Frontiers in Oncology

Structural perspectives on recent breakthrough efforts toward direct drugging of RAS and acquired resistance

Review

Author: Tran, Timothy H ; Smalley, Tracess B ; Lokhandwala, Jameela

The Kirsten rat sarcoma viral oncoprotein homolog (KRAS) is currently a primary focus of oncologists and translational scientists, driven by exciting results with KRAS-targeted therapies for non-small cell lung cancer (NSCLC) patients. While KRAS mutations continue to drive high cancer diagnosis and death, researchers have developed unique strategies to target KRAS variations. Having been investigated over the past 40 years and considered “undruggable” due to the lack of pharmacological binding pockets, recent breakthroughs and accelerated FDA approval of the first covalent inhibitors targeting KRASG12C, have largely sparked further drug development. Small molecule development has targeted the previously identified primary location alterations such as G12, G13, Q61, and expanded to address the emerging secondary mutations and acquired resistance. Of interest, the non-covalent KRASG12D targeting inhibitor MRTX-1133 has shown promising results in humanized pancreatic cancer mouse models and is seemingly making its way from bench to bedside. While this manuscript was under review a novel class of first covalent inhibitors specific for G12D was published, These so-called malolactones can crosslink both GDP and GTP bound forms of G12D. Inhibition of the latter state suppressed downstream signaling and cancer cell proliferation in vitro and in mouse xenografts. Moreover, a non-covalent pan-KRAS inhibitor, BI-2865, reduced tumor proliferation in cell lines and mouse models. Finally, the next generation of KRAS mutant-specific and pan-RAS tri-complex inhibitors have revolutionized RAS drug discovery. This review will give a structural biology perspective on the current generation of KRAS inhibitors through the lens of emerging secondary mutations and acquired resistance.

100 Deals associated with BI-2865

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Memorial Sloan Kettering Cancer Center	31 May 2023
Neoplasms	Preclinical	AT	Boehringer Ingelheim GmbH	31 May 2023
KRAS mutation-related tumors	Discovery	US	Memorial Sloan Kettering Cancer Center	19 Jun 2023

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