P1/2, N=65, Terminated, Sanofi | Active, not recruiting --> Terminated; Sponsor's decision not related to any safety concern

Besides, we proved that cisplatin could activate SHP2 and SHP099 increased sensitivity to cisplatin in GC. Taken together, our results provide evidence that the SHP2/PKM2/AMPK axis exerts a key role in GC progression and glycolysis and could be a viable therapeutic approach for the therapy of GC.

P1, N=53, Active, not recruiting, Pfizer | N=36 --> 53

P1/2, N=410, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting | Trial completion date: Jul 2029 --> May 2024 | Trial primary completion date: Aug 2027 --> May 2024

P1, N=68, Recruiting, Suzhou Genhouse Bio Co., Ltd. | Not yet recruiting --> Recruiting | Trial primary completion date: Feb 2024 --> Dec 2024

P2, N=72, Not yet recruiting, Suzhou Genhouse Bio Co., Ltd.

P1, N=130, Active, not recruiting, Navire Pharma Inc., a BridgeBio company | Recruiting --> Active, not recruiting

P1/2, N=94, Recruiting, Suzhou Genhouse Bio Co., Ltd.

At days 8 and 15, respectively, 310 and 42 significant differentially expressed genes were identified between groups (false discovery rate adjusted p1). SFX-01 treatment did not improve clinical status or modulate key Nrf2 targets in patients with CAP primarily due to SARS-CoV-2 infection.

P1, N=0, Withdrawn, Novartis Pharmaceuticals | N=48 --> 0 | Trial completion date: Jun 2024 --> Jul 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Jun 2024 --> Jul 2025

P1, N=0, Withdrawn, Novartis Pharmaceuticals | N=48 --> 0 | Trial completion date: Jun 2024 --> Jun 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Jun 2024 --> Jun 2025

The combination of the HDAC inhibitor SAHA and SHP2 inhibitor SHP099 suppressed the progression of lung cancer markedly in vitro and in vivo. Therefore, we revealed the epigenetic silencing mechanism of PTPRR and demonstrated that combination therapy targeting HDAC and SHP2 might represent a novel strategy to treat RAS-mutant lung cancer.

P2, N=20, Ongoing, Jacobio Pharmaceuticals Co., Ltd.

In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors...Furthermore, the combination therapy of compound 4b and KRAS inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells...Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRAS mutant non-small cell lung cancer.Communicated by Ramaswamy H. Sarma.

NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor-suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6C monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.

P1, N=122, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business reasons

P1/2, N=65, Active, not recruiting, Sanofi | Trial completion date: Jul 2024 --> Mar 2024 | Trial primary completion date: Jul 2024 --> Mar 2024

P1, N=255, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Apr 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

These effects can be overcome through the use of TGFβ-targeted therapies. Consequently, our findings provide a rationale for combining SHP2 and TGFβ inhibitors to enhance tumour responses leading to improved patient outcomes.

In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

P1, N=36, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=196 --> 36

P1, N=200, Active, not recruiting, Erasca, Inc. | Recruiting --> Active, not recruiting

Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

In addition, several SHP2 inhibitors are currently in clinical trials for cancer treatment. This review aims to provide an overview of the current research on SHP2 inhibitors, including their mechanism of action, structure-activity relationships, and clinical development, focusing on immune modulation effects and novel therapeutic strategies in the immune-oncology field.

In NF1 mutant glioblastoma in vitro and in vivo models, cellular response to both upstream (SHP2) and downstream (MEK) inhibition are mediated by Ras/Raf/MEK signaling while RMC-4550 alone uniquely regulates a focal adhesion network associated with EMT and demonstrates improved efficacy in vivo.

To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments.

We found that the SHP2 inhibitors RMC-4550 and SHP099 enhanced growth inhibition of MPN model cell lines (e.g., SET2 and UKE1) in combination with ruxolitinib, effectively preventing ruxolitinib persistent growth. Importantly, the combination of SHP2 inhibition using RMC-4550 with JAK2 inhibition using ruxolitinib for 4 weeks in wildtype mice was well tolerated with respect to hematologic parameters and exemplified by no effect on body weight (Panel B). Given SHP2 inhibitors are already undergoing clinical evaluation in patients with solid tumors, our findings suggest that SHP2 is a therapeutic target with potential to be rapidly translated to clinical assessment for MPN patients.

Our group showed a selective response (~40%) with the PD-1 blocking antibody pembrolizumab in patients with RT, particularly after prior exposure to ibrutinib (Ding et al, Blood, 2017)...SHP-1 (TPI-1) and SHP-1+SHP-2 (TPI-1+TNO155) inhibitor treatment promoted OCI-LY19 cell death and led to recovery of phosphorylation on ATM, Chk-2 and p53 in these cells... Our data showed robust PD-1 expression in patients with Richter transformation from CLL to DLBCL. PD-1 overexpression in DLBCL lymphoma cell lines enhanced cell proliferation in vitro and in vivo. Further investigation identified that PD-1 modified the phosphorylation/function of SHP phosphatases and thereby regulated p53 pathways (Figure 1).

The addition of SHP099 to sorafenib decreased the expected ERK reactivation in a dose-dependent manner...The combination of SHP099 with gilteritinib group resulted in a statistically significantly lower leukemia burden compared to either treatment alone and the vehicle control...While daunorubicin or cytarabine alone had little effect on the level of phosphorylated ERK, the addition of SHP099 decreased ERK activation and the combination synergized to exert greater to decrease proliferation and increase apoptosis...The finding that SHP099 synergized with both FLT3 TKI and chemotherapy agents in different FLT3-mutated AML models speaks to the versatile efficacy of SHP2 inhibition in multiple AML models. Taken together, the data suggests that SHP2 inhibition can help overcome both adaptive and acquired resistance in FLT3/ITD AML and is a candidate to try to improve patient outcomes.

P1/2, N=410, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting

Our study demonstrates that exosomal miR-138-5p from irradiated tumor cells can modulate macrophage polarization by targeting SHP-2. And SHP-2 negatively regulates glycolysis and polarize macrophage to an M2 phenotype by SHP-2/PKM2(Tyr105) (Ser37)/β-catenin/LDHA/Glut-1 axis.

We report on the generation of MPN BM in an ex vivo bioreactor system with Jak2V617F stem/progenitors engrafting into engineered niches and recapitulating MPN. We observed that SHP2 inhibition with TNO155 had differential effects to ruxolitinib primarily affecting LSK and erythroid compartments, which suggests a translational potential of dual JAK2/SHP2 inhibition in MPN. A humanized bioreactor system engineered from primary MPN patient cells is being setup.

We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

3 Methods In this study we use a novel, covalent tri-complex KRASG12C(ON) inhibitor, RM-029, which targets KRASG12C in the active state in combination with the SHP2 inhibitor RMC-4550 (both preclinical tool compounds), and studied their in vivo anti-tumor activity on transplantable KRAS-mutant lung cancer mouse models of varying immunogenicities...Results In vitro, RM-029 exhibited higher potency for inhibition of cell viability than the KRASG12C(OFF) inhibitor MRTX849 in both human and murine NSCLC cell lines...This is accompanied by significant TME reorganization, including depletion of immunosuppressive innate immune cells and recruitment and activation of T and NK cells. Conclusions Overall, our preclinical results demonstrate the potential of the combination of KRASG12C(ON) inhibitors with SHP2 inhibitors and/or immune checkpoint blockade not only by targeting KRAS-driven proliferation in tumour cells but by stimulating anti-tumour immunity.

Conclusions In general, SHP099 can not only boost the tumor-cytotoxicity effect and overcome the drug resistance of AZD4547, but also activate cytotoxic T lymphocytes to kill tumor cells in FGFR2-alterated gastric cancers. Our results demonstrate the utility and feasibility of combining SHP2 to FGFR2 inhibitors for GC patients with FGFR2 alteration.

To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components...Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic.

P1/2, N=410, Not yet recruiting, Bristol-Myers Squibb

ChiP-RS is fabricated by utilizing macrophage-targeting chimeric peptide (ChiP) to load Toll-like receptor agonists (R848) and Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor (SHP099)...In vitro and in vivo findings demonstrate a superior suppression effect of ChiP-RS against metastatic tumors without systemic side effects. Such a simple but effective nanoplatform provides sophisticated synergism for immunotherapy, which may facilitate the development of translational nanomedicine for metastatic tumor treatment.

Thus, the SHP099 (a SHP-2 inhibitor) can uptake and utilization of glucose by SHP-2/PKM2(Tyr105) (Ser37)/ß-catenin/LDHA/Glut-1 axis, suggesting that SHP099 plays positive roles on glycolysis and M1-polarized... Our study demonstrates that exosomal miR-138-5p from irradiated tumor cells can modulate macrophage polarization by targeting SHP-2. And SHP-2 negatively regulates glycolysis and polarize macrophage to an M2 phenotype by SHP-2/PKM2(Tyr105) (Ser37)/ß-catenin/LDHA/Glut-1 axis.

P1, N=172, Recruiting, Genentech, Inc. | Not yet recruiting --> Recruiting

PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers...This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda.