The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models.

Abstract

3616 Background: RET fusions/mutations drive oncogenesis in lung and thyroid cancers, and several other malignancies. Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. On-target resistance includes the acquisition of solvent front mutations (SFMs i.e. RET G810 substitutions). TPX-0046 is a structurally differentiated RET inhibitor that is potent against a range of RET fusions and mutations including SFMs. Methods: The rationally-designed, compact, macrocyclic RET/SRC inhibitor TPX-0046 was characterized in RET-driven in vitro and in vivo tumor models. Results: In enzymatic assays, TPX-0046 showed low nanomolar potency against wild-type RET and 18 RET mutations/fusions. It was potent against SRC and spared VEGFR2/KDR. TPX-0046 inhibited RET phosphorylation (IC50 < 10 nM) in tumor cell lines (LC2/ad, CCDC6-RET; TT, RET C634W) and Ba/F3 engineered RET models (WT, G810R). In cell proliferation assays, TPX-0046 inhibited KIF5B-RET Ba/F3, LC2/ad, and TT cells with IC50 values ~1 nM. Ba/F3 RET engineered cells with SFMs (e.g. G810C/R/S) were potently inhibited by TPX-0046 (mean proliferation IC50 1–17 nM). TPX-0046 demonstrated marked in vivo anti-tumor efficacy in RET-driven cell-derived and patient-derived xenograft tumor models. In a Ba/F3 KIF5B-RET xenograft model, a single dose of 5 mg/kg TPX-0046 inhibited > 80% of RET phosphorylation (corresponding mean free plasma concentration: 51 nM). At 5 mg/kg BID, tumor regression was observed in RET-dependent xenograft models, including those that harbor RET SFMs: TT, CTG-0838 PDX (NSCLC, KIF5B-RET), CR1520 PDX (CRC, NCOA4-RET), Ba/F3 KIF5B-RET, and Ba/F3 KIF5B-RET G810R. Conclusions: TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391).

Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

“…TPX-0046 is a 3rd generation, highly selective TKI tested, so far, in drug-resistant and naïve RET -driven cancer models [ 128 ]. This drug is very promising, especially for cases in which a resistance to the other TKIs has been developed through the induction of RET- 810 mutation.…”

Tyrosine Kinase Receptors in Oncology

“…Other RET-specific TKIs, like pralsetinib (BLU-667, which selectively inhibits RET), are being tested in the phase I dose-escalation and phase II expansion ARROW trial, with promising results, showing an ORR of 73% in RET-mutant MTC patients and an ORR of 91% in 11 patients with RET-fused DTC [ 243 ]. Interestingly, the TPX-0046, a potent and selective next-generation TKI with activity against SRC kinase, has emerged as a targeted agent to potentially overcome resistance to first-generation selective RET inhibitors [ 244 , 245 ].…”

Tumor‐agnostic inhibitors in oncology: A new phase for precision medicine

“…[ 14 ] Although selpercatinib and pralsetinib are approved by FDA in 2020, TPX‐0046, the newly RET/SRC dual inhibitor, is also under phase I/II development (NCT04161391) in adult subjects with advanced solid tumors harboring RET fusions or mutations. [ 15 ]…”

“…[14] Although F I G U R E 3 Structures of promising small-molecule kinase inhibitor as tumor-agnostic therapy selpercatinib and pralsetinib are approved by FDA in 2020, TPX-0046, the newly RET/SRC dual inhibitor, is also under phase I/II development (NCT04161391) in adult subjects with advanced solid tumors harboring RET fusions or mutations. [15] Fibroblast growth factor receptor (FGFR) kinase family is also a drug target for tissue-agnostic treatment. [16] The function of FGFRs are related to cell proliferation and differentiation during development and tissue repair.…”

“…By using diphenylsilane, iridium coupling reagents and (R)-iPr-PHOX, pyrrole 13 was asymmetrically reduced to (R)-2-(2,5-difluorophenyl)-pyrrolidine (14). Finally, the pyrrolidine 14 was treated with D-malic acid to give the (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate complex (15). In the last stage, the chloropyrimidine 9 coupled with complex 15 under basic conditions to yield the S N Ar product 16.…”